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Translational Cancer Research: Bench, Bedside, and Community

Translational Cancer Research
Reported by
Megan Stephan

Posted March 30, 2009


Cancer cells can use many strategies to defeat the normal checks and balances of cell growth and death. Some cancer cells within tumors can resemble stem cells, an idea explored in recent research on the mechanisms of tumor formation, invasion of surrounding tissues, and metastasis.

These concepts were discussed by the researchers who presented at the 22nd Annual International Symposium of the Hunter College Center for Gene Structure and Function, held in New York on January 22, 2009. The day-long symposium included talks that ranged from the genetic differences in cancers among people of different races, to molecular mechanisms used by cancer cells for metastasis and the development of a molecularly targeted therapy for prostate cancer. Along the way, speakers also shed light on the disparities in cancer health care faced by minorities here in the United States and by people living in underdeveloped countries throughout the world.

Use the tabs above to find a meeting report and multimedia from this event.



This conference and eBriefing were made possible with support from the Weill Cornell Medical College, Clinical & Translational Science Center (CTSC), Hunter College of the City University of New York, the National Institutes of Health, National Center for Research Resources, Research Centers in Minority Institutions – G12-RR-003037, and the Clinical and Translational Science Awards – UL1RR024996.


Web Sites

2007 National Healthcare Quality & Disparities Reports
Annual report on health care disparities prepared by the Agency for Healthcare Research and Quality (AHRQ) of the US Department of Health and Human Services.

American Cancer Society's Cancer Facts and Figures
This annual cancer report includes information on racial differences in cancer mortality.

Genetic Testing for BRCA1 and BRCA2: It's Your Choice
National Cancer Institute Fact Sheet on breast cancer susceptibility genes BRCA1 and -2.

International Union Against Cancer
International nongovernmental organization dedicated to the fight against cancer.

The Niche: Cancer Stem Cells Stories
Compendium of news articles on cancer stem cells from Nature Reports Stem Cells.

Prostate Cancer
A National Library of Medicine information page with links to prostate cancer resources.

The TP53 Web Site: p53 Information
Compilation of current knowledge on p53, its roles in the cell and in cancer, and its interaction with MDM2.

Journal Articles

Nature, Nurture, and Breast Cancer

Fackenthal JD, Olopade OI. 2007. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat. Rev. Cancer 7: 937-948.

Huo D, Adebamowo CA, Ogundiran TO, et al. 2008. Parity and breastfeeding are protective against breast cancer in Nigerian women. Br. J. Cancer 98: 992-996.

Huo D, Kim HJ, Adebamowo CA, et al. 2008. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans. Breast Cancer Res. Treat. 110: 367-376.

Olopade OI, Schwartsmann G, Saijo N, Thomas CR Jr. 2006. Disparities in cancer care: a worldwide perspective and roadmap for change. J. Clin. Oncol. 24: 2135-2136. Full Text

Zhang B, Fackenthal JD, Niu Q, et al. 2009. Evidence for an ancient BRCA1 mutation in breast cancer patients of Yoruban ancestry. Fam. Cancer 8: 15-22.

A Historical Perspective of Breast Cancer Health Statistics

Brawley OW. 2006. Lung cancer and race: equal treatment yields equal outcome among equal patients, but there is no equal treatment. J. Clin. Oncol. 24: 332-333. Full Text

Brawley OW, Berger MZ. 2008. Cancer and disparities in health: perspectives on health statistics and research questions. Cancer 113: 1744-1754.

Flowers CR, Glover R, Lonial S, Brawley OW. 2007. Racial differences in the incidence and outcomes for patients with hematological malignancies. Curr. Probl. Cancer 31: 182-201.

Gabram SG, Lund MJ, Gardner J, et al. 2008. Effects of an outreach and internal navigation program on breast cancer diagnosis in an urban cancer center with a large African-American population. Cancer 113: 602-607.

Kauh J, Brawley OW, Berger M. 2007. Racial disparities in colorectal cancer. Curr. Probl. Cancer 31: 123-133.

Smith RA, Cokkinides V, Brawley OW. 2009. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J. Clin. 59: 27-41. Full Text

Breast Cancer Mysteries

Norton L. 2008. Cancer stem cells, self-seeding, and decremented exponential growth: theoretical and clinical implications. Breast Dis. 29: 27-36.

Norton L, Massagué J. 2006. Is cancer a disease of self-seeding? Nat. Med. 12: 875-878.

Simon R, Norton L. 2006. The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens. Nat. Clin. Pract. Oncol. 3: 406-407.

Traina TA, Theodoulou M, Feigin K, et al. 2008. Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer. J. Clin. Oncol. 26: 1797-1802.

The Worldwide Fight Against Cancer: Problems and Hopes

Cavalli F. 2008. The World Cancer Declaration: a roadmap for change. Lancet Oncol. 9: 810-811.

Cavalli F. 2006. Cancer in the developing world: can we avoid the disaster? Nat. Clin. Pract. Oncol. 3: 582-583. (PDF, 92.7 KB) Full Text

Ribeiro RC, Steliarova-Foucher E, Magrath I, et al. 2008. Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study. Lancet Oncol. 9: 721-729.

Invasion, Metastasis, and Stem Cells

Ben-Porath I, Thomson MW, Carey VJ, et al. 2008. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40: 499-507.

Karnoub AE, Dash AB, Vo AP, et al. 2007. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557-563.

Ince TA, Richardson AL, Bell GW, et al. 2007. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12: 160-170. Full Text

Mani SA, Guo W, Liao MJ, et al. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704-715.

Yang J, Weinberg RA. 2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14: 818-829.

Consequences of Utilization of Stem Cell Pathways by Cancer Cells

Cho RW, Clarke MF. 2008. Recent advances in cancer stem cells. Curr. Opin. Genet. Dev. 18: 48-53.

Cho RW, Wang X, Diehn M, et al. 2008. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26: 364-371. Full Text

Diehn M, Cho RW, Lobo NA, et al. 2009. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature Feb 4. [Epub ahead of print]

Lobo NA, Shimono Y, Qian D, Clarke MF. 2007. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23: 675-699.

Prince ME, Sivanandan R, Kaczorowski A, et al. 2007. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 104: 973-978. Full Text

Pharmacogenomics for Cancers with Compromised p53

Arva NC, Gopen TR, Talbott KE, et al. 2005. A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J. Biol. Chem. 280: 26776-26787. Full Text

Arva NC, Talbott KE, Okoro DR, et al. 2008. Disruption of the p53-Mdm2 complex by Nutlin-3 reveals different cancer cell phenotypes. Ethn. Dis. 18: S2-1-8.

Boamah EK, White DE, Talbott KE, et al. 2007. Mitomycin-DNA adducts induce p53-dependent and p53-independent cell death pathways. ACS Chem. Biol. 2: 399-407.

Targeted Treatment of Metastatic Prostate Cancer with a Radiolabeled Antibody

Bander NH, Milowsky MI, Nanus DM, et al. 2005. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J. Clin. Oncol. 23: 4591-4601. Full Text

David KA, Milowsky MI, Kostakoglu L, et al. 2006. Clinical utility of radiolabeled monoclonal antibodies in prostate cancer. Clin. Genitourin Cancer 4: 249-256.

Milowsky MI, Nanus DM, Kostakoglu L, et al. 2007. Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors. J. Clin. Oncol. 25: 540-547. Full Text

Rajasekaran SA, Anilkumar G, Oshima E, et al. 2003. A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol. Biol. Cell. 14: 4835-4845. Full Text

Ross JS, Gray KE, Webb IJ, et al. 2005. Antibody-based therapeutics: focus on prostate cancer. Cancer Metastasis Rev. 24: 521-537.

Vallabhajosula S, Goldsmith SJ, Kostakoglu L, et al. 2005. Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies: effect of multiple treatments on myelotoxicity. Clin. Cancer Res. 11: 7195s-7200s. Full Text

Keynote Speakers

Robert A. Weinberg, PhD

MIT and Whitehead Institute for Biomedical Research
e-mail | web site | publications

Robert Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the director of the Ludwig Center for Molecular Oncology at the Massachusetts Institute of Technology (MIT). He is an internationally recognized authority on the genetic basis of human cancer. Weinberg and his colleagues isolated the first human cancer-causing gene, the ras oncogene, and the first known tumor suppressor gene, Rb, the retinoblastoma gene. Weinberg is the author or editor of five books and more than 350 articles. He is an elected member of the U.S. National Academy of Sciences and the Institute of Medicine and is a fellow of the American Academy of Arts and Sciences.

Among Weinberg's honors are the Discover magazine 1982 Scientist of the Year, the National Academy of Sciences/U.S. Steel Foundation Award in Molecular Biology, the Sloan Prize of the General Motors Cancer Research Foundation, the Bristol-Myers Award for Distinguished Achievement in Cancer Research, the Landon Prize of the American Association for Cancer Research, the Gairdner Foundation International Award, the Keio Medical Foundation Prize, and the 1997 National Medal of Science. He has served on scientific advisory boards for the Institute of Molecular Pathology in Vienna, Austria, and the Massachusetts General Hospital in Boston.

Weinberg received his PhD degree in biology from MIT in 1969. He did postdoctoral research at the Weizmann Institute in Rehovoth, Israel, and the Salk Institute in La Jolla, California, and then returned to MIT in 1972. In 1982, he was appointed professor of biology at MIT and also became one of the five founding members of the Whitehead Institute. He has been an American Cancer Society Research Professor at Whitehead and MIT since 1985.

Olufunmilayo I. Olopade

University of Chicago Medical Center
e-mail | web site | publications

The Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics at the University of Chicago and associate dean for global health, Olufunmilayo (Funmi) Olopade epitomizes the "bench-to-bedside" philosophy of research in her application ofscientific discoveries to clinical medicine and has seamlessly integrated her findings into clinical applications. As a hematologist/oncologist, Olopade specializes in cancer risk assessment and treatment of aggressive breast cancers that disproportionately affect young women. A member of many professional societies, including the Association of American Physicians, Olopade has national and international recognition as a cancer geneticist. A speaker in much demand, she effectively communicates the benefits of advanced cancer research, inspires students and colleagues, and provides a role model for women scientists worldwide.

Olopade received her medical degree with distinction from the University of Ibadan in Nigeria. She came to the United States as a resident in internal medicine at Cook County Hospital, Chicago, where she was named chief medical resident. Olopade completed her postdoctoral fellowship training in the section of Hematology/Oncology at the University of Chicago and was appointed to the faculty in 1991. Olopade is founding director of the Cancer Risk Clinic in the Department of Medicine and holds many other faculty, hospital, and administrative posts. Olopade is the recipient of numerous honors and awards including the James S. McDonnell Foundation Scholar award, the Doris Duke Distinguished Clinical Scientist award, and a 2005 MacArthur Fellowship "genius" grant.


Otis Brawley, MD

American Cancer Society
e-mail | web site | publications

As the chief medical officer and executive vice president of the American Cancer Society, Otis Webb Brawley is responsible for promoting the goals of cancer prevention, early detection, and quality treatment through cancer research and education. As an acknowledged global leader in the field of health disparities research, Brawley is a key leader in the Society's work to eliminate disparities in access to quality cancer care.

Brawley currently serves as professor of hematology, oncology, medicine, and epidemiology at Emory University. From 2001 to 2007, he was medical director of the Georgia Cancer Center for Excellence at Grady Memorial Hospital in Atlanta, and deputy director for cancer control at Winship Cancer Institute at Emory University. He has also co-chaired the U.S. Surgeon General's Task Force on Cancer Health Disparities, and filled a variety of capacities at the National Cancer Institute (NCI), most recently serving as assistant director.

Currently, Brawley serves as a member of the Centers for Disease Control and Prevention Breast and Cervical Cancer Early Detection and Control Advisory Committee. He served as a member of the Food and Drug Administration Oncologic Drug Advisory Committee and chaired the NIH Consensus Panel on the Treatment of Sickle Cell Disease. He is listed by Castle Connelly as one of America's Top Doctors for Cancer. Among numerous other awards, he was a Georgia Cancer Coalition Scholar and received the Key to St. Bernard Parish for his work in the U.S. Public Health Service in the aftermath of Hurricane Katrina. Brawley is a graduate of University of Chicago, Pritzker School of Medicine.

Larry Norton, MD

Memorial Sloan-Kettering Cancer Center
e-mail | web site | publications

Larry Norton is deputy physician-in-chief and director of breast cancer programs at Memorial Sloan-Kettering Cancer Center. He is scientific director of the Breast Cancer Research Foundation (BCRF), and has served as chairman of the BCRF Medical Advisory Board since its inception in 1993. Norton is past president of the American Society of Clinical Oncology, and chair of the ASCO Foundation. A presidential appointee to the National Cancer Advisory Board of the NCI (1998–2004), he is the first incumbent of the Norna S. Sarofim Chair in Clinical Oncology at MSKCC and recipient of the American Society of Clinical Oncology's 2004 David A. Karnofsky Memorial Award. Norton has received numerous honorary visiting professorships and has been honored by many organizations.

After receiving his MD from the College of Physicians and Surgeons, Columbia University, he trained in Internal Medicine at the Albert Einstein College of Medicine. He then served as a clinical associate and investigator at the NCI prior to joining the faculty of the Mount Sinai Medical Center in New York from 1977–1988. He is currently professor of medicine at Weill Medical College of Cornell University.

Norton has served on or chaired numerous committees of governmental and professional organizations, including the NCI's Cancer Clinical Investigations Review Committee, its Cooperative Breast Cancer Tissue Resource (Registry), and the Consensus Development Conference on Treatment of Early Stage Breast Cancer (1990). He has also served on several committees of the Institute of Medicine of the National Academy of Sciences. Norton is on the editorial board of several medical publications, and is an active clinical and laboratory investigator. He is the coauthor of the Norton-Simon Model, which has broadly influenced cancer treatment and research for over 25 years.

Franco Cavalli, MD

Oncology Institute of Southern Switzerland
e-mail | web site | publications

Franco Cavalli obtained his MD from the Medical University, Bern (Switzerland) and upon completing his studies he joined the Department of Internal Medicine, Inselspital, Bern. He then served at the Institute of Medical Oncology at the same institution until 1978. He has been head of the Division of Oncology, Ospedale San Giovanni, Bellinzona (Switzerland) since 1978 and was appointed honorary professor in internal medicine, specializing in oncology, on the medical faculty at the University of Bern. He has been director of the Oncology Institute of Southern Switzerland (IOSI), Bellinzona since 1999.

His expertise is also called upon by countless scientific boards, committees, and task forces. The most recent include the scientific board of the Istituto Nazionale dei Tumori Regina Elena, on which he serves as member and the scientific committee of the European School of Oncology (ESO) in which he serves in the capacity of vice-president. He was appointed president of the International Union Against Cancer (UICC) in 2006 and also currently serves as board member of ECCO—the European Cancer Organization. Cavalli is author of 500 publications, work which has been recognized through several awards and prizes of prestige. The most recent include the Swiss Award (Man of the Year) for Societal Merits, and the Montaigne Prize from the Toepfer Foundation in Hamburg.

Michael F. Clarke, MD

Stanford Institute for Stem Cell and Regenerative Medicine
e-mail | web site | publications

Michael Clarke is an international leader in the area of stem cell biology. He is the associate director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. In addition to his clinical duties in the Division of Oncology, Clarke maintains a laboratory focused on two areas of research: 1) the control of self-renewal of normal stem cells and their malignant counterparts; and 2) the identification and characterization of cancer stem cells.

In particular, his laboratory is pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. His laboratory has discovered that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. By investigating the pathways upstream and downstream of Bmi-1, the laboratory is actively investigating the molecular pathways that regulate self-renewal. His focus is to aid in the development of more effective treatment therapies for various forms of cancer. Clarke's group has developed a technique that allows the isolation and characterization of tumorigenic and non-tumorigenic populations of cancer cells present in human breast, colon, and head and neck cancer tumors.

Jill Bargonetti, PhD

Hunter College, City University of New York
e-mail | publications

Molecular biologist Jill Bargonetti is a cancer researcher and tenured professor at the City University of New York with a joint appointment at Hunter College and the Graduate Center. Bargonetti has done extensive research on the p53 protein, which assists in the suppression of tumor cell growth. Mutation of the p53 gene is found in numerous different tumor types. Prior to arriving on the Hunter College campus in 1994, Bargonetti was a postdoctoral fellow at Columbia University (1990–1994). Bargonetti holds a PhD in molecular biology from New York University.

Awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997, Bargonetti has received numerous research grants from the National Science Foundation and the National Institutes of Health, as well as grants from the American Cancer Society and the Department of Defense Breast Cancer Research program. The most recent prestigious grant funding is from the Breast Cancer Research Foundation. Bargonetti was a member of the National Cancer Policy Board (a board of the Institution of Medicine and National Research Council of the National Academies) from 2002 until 2005.

Neil Bander, MD

Weill Cornell Medical College/ New York Presbyterian Hospital
e-mail | web site | publications

Neil Bander is the Bernard and Josephine Chaus Professor of Urologic Oncology and director of the Urological Oncology Research Program at Weill Medical College of Cornell University. He is also a member in the Department of Urology at Memorial Sloan-Kettering Cancer Center.

Bander graduated from the Johns Hopkins University and received his MD degree from the University of Connecticut. After completing surgical and urological residencies, Bander completed an NIH immunology training fellowship in the laboratory of Lloyd Old and was a Ferdinand C. Valentine Fellow in urological oncology under Willet F. Whitmore, Jr., at Memorial Sloan-Kettering Cancer Center. In 1983, he joined the faculty at Cornell Medical Center.

Bander has authored more than 100 peer-reviewed publications in the fields of monoclonal antibodies, immunotherapy, and urological cancers. He is considered the world's authority on the use of antibodies for imaging and therapy of patients with urological malignancies. He serves on several journal editorial boards, review committees for the Department of Defense Prostate Cancer Program, NIH, the Kidney Cancer Association Medical Advisory Board, and is a member of numerous professional societies and several biotech advisory boards. His contributions have been recognized by the American Urological Association as well as the Urological Associations of Germany and Japan. He has won several awards, including the Society of Surgical Oncology Ewing Research Award, the German Urology Association Research Award, and eight consecutive Prostate Cancer Foundation Awards, and has been a visiting professor on four continents.

Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.

Robert A. Weinberg, Whitehead Institute for Biomedical Research, The Massachusetts Institute of Technology


  • Transformed cells can produce different types of cancers depending on the identity of the cells from which they are derived.
  • Cancer cells must carry out a complex series of biological steps in order to become invasive, form micrometastases, and colonize new tissues as full blown metastases.
  • Many of these steps are made possible by the acquisition of new properties associated with an epigenetically controlled gene expression program known as the epithelial-mesenchymal transition.
  • The epithelial-mesenchymal transition also plays a key role in embryonic development, suggesting that cancer cells co-opt the developmental programs of normal stem cells in order to become invasive and metastasize.

A deadly process

Much of cancer research focuses on the process of metastasis, which is ultimately responsible for 90% of cancer-associated deaths. Robert Weinberg and his group at the Whitehead Institute for Biomedical Research and MIT are studying the steps that allow localized cancers to become invasive and spread to other parts of the body. Identification of genetic or epigenetic changes that lead to metastasis may one day lead to new therapies to prevent this deadly process.

The ability to metastasize may depend on differentiation programs already present in specific types of cells.

Metastasis is a process that requires cancer cells to adapt to new environments. To better understand how such adaptation occurs, Weinberg and his group have studied what happens to normal human mammary epithelial cells when they are grown under different culture conditions. When cells grown under two different conditions are transformed into cancer cells by the introduction of oncogenes, they produce two different types of breast cancer, adenocarcinoma and squamous cell carcinoma, despite the fact that they have received identical genetic changes. Adenocarcinomas are highly metastatic while squamous cell cancers are not. These results suggest that the normal cell of origin is an important determinant of a cancer's phenotype, and that the ability to metastasize may depend on differentiation programs already present in specific types of cells.

One property of the original tissue that appears to play an important role in this process is the frequency of stem cells in the population. In a normal epithelial cell population, only the stem cells have the capacity to both differentiate and renew themselves. In tumors, only stem cells have the ability to seed a new tumor. The frequency of normal stem cells in the original tissue may affect the frequency of stem cells in the cancer that develops from it, and tumors with more stem cells are likely to grow faster and be more aggressive.

Developmental programs gone wrong

Metastasis takes place through a series of biological steps, which include the cancer's initial invasion of surrounding tissue, entry into and transport of cancer cells through the blood stream, exit from the blood into a new tissue, and the formation of a micrometastasis. The micrometastasis may grow to become a full blown metastatic tumor by adapting to, or colonizing, its new tissue microenvironment. These are all complex biological tasks, and the last step, colonization, is also the least efficient. It has been shown that many cancer patients carry large numbers of micrometastases, most of which fail to take hold and grow in a new location. Thus interfering with the colonization step could be a very effective method of preventing the harm caused by clinically detectable metastases.

Stepwise progress of cancer cells from primary tumor to full-blown metastasis.

Weinberg and his group have made significant progress toward understanding the underlying molecular changes involved in metastatic dissemination by careful study of tumor cells introduced into mice, known as xenografts. They have observed that some epithelial-like breast cancer cells make a transition to a mesenchymal form as the new tumor grows. This transition occurs specifically along the outside edges of the tumor xenograft, suggesting that signals from the surrounding stromal environment are involved in promoting it. This epithelial-mesenchymal transition, or EMT as it is called, is a complex genetic program that involves the acquisition of motility, invasiveness, and an increased resistance to apoptosis. Weinberg and his group have identified a number of transcription factors that are involved in programming this process as tumor cells adapt to their surrounding microenvironment.

The EMT is an ancient genetic program that is also important in embryogenesis. Weinberg's findings suggest that the EMT is used as a "pre-assembled package" of gene expression changes that can be appropriated by the cancer cells for their own use. Many of the transcription factors identified as choreographing this process exert pleiotropic effects, promoting multiple phenotypic changes in cancer cell phenotype, and enabling cancer cells to complete most of the steps of cancer cell mobilization, from invasion up to colonization. Weinberg pointed out that if the expression of these transcription factors can be induced by external signals, then further mutations may not be required in order for cancer cells to negotiate most of the steps of the invasion-metastasis process.

Melanocytes, mammary stem cells, and metastases

These types of changes are not limited to epithelial cells. Weinberg and his group have shown that a different embryonic transcription factor is involved in the transformation of melanocytes from skin. Experimental transformation of these cells with a set of introduced oncogenes generates numerous metastases, while transformation of epithelial cells with the same introduced genetic changes generates cells that are non- or weakly metastatic, again showing that the identity of the normal cell of origin is an important determinant of eventual metastatic behavior. Melanocytes have a distinct developmental program available to them, one that directs their migration as single cells from the primitive neural crest during normal embryonic development.

Cancerous epithelial cells that undergo the EMT resemble mammary epithelial stem cells.

These gene expression changes can also be linked back to the characteristics of stem cells in the original tissues. Cancerous epithelial cells that undergo the EMT resemble mammary epithelial stem cells in their molecular characteristics and in their ability to replicate. On the flip side, cancer stem cells isolated from immortalized mammary epithelial cells, as well as from human breast cancers, express mesenchymal markers, suggesting that they may have arisen as a result of an EMT transition.

Taken together, Weinberg's observations suggest that while the initial steps needed to initiate a cancer may depend on mutations, further steps in the invasive and metastatic process may be accomplished simply by accessing pre-programmed developmental processes that are used by each cell type during embryogenesis. This transition to a more stem cell-like phenotype confers on cancer cells the ability to move about the body, colonize other tissues, and replicate as needed to form metastases.

These findings have important implications for cancer therapies. Most currently used chemotherapeutics primarily kill the non-stem cells in the cancer, which could actually permit the regeneration of the tumor by the cancer stem cells. Thus Weinberg and his group are looking for compounds that kill cancer stem cells preferentially, since these are the cells that are most likely to metastasize and lead to the more deadly consequences of cancer.

Cancer cells can use many strategies to defeat the normal checks and balances of cell growth and death. The initiation of cancer often requires the accumulation of mutations, which can be spontaneous, such as many of the mutations in the p53 tumor suppressor gene, or inherited, such as mutations in the breast cancer susceptibility genes BRCA1 and BRCA2.

Once a cell has become cancerous, its stratagems may include wholesale co-opting of cellular programs originally intended for other purposes. Cancer cells can remake themselves to perform functions similar to stem cells, the multipotent progenitor cells that give tissues and organs their shape and function during development, and replenish them as wear and tear makes necessary. The idea that certain cancer cells within tumors can resemble stem cells has given rise to extensive recent research that has shed light on the mechanisms of tumor formation, invasion of surrounding tissues, and metastasis.

These concepts were explored by the researchers who spoke at the 22nd Annual International Symposium of the Hunter College Center for Gene Structure and Function, held in New York on January 22, 2009. The day-long symposium included talks that ranged from the genetic differences in cancers among people of different races, to molecular mechanisms used by cancer cells for metastasis and the development of a molecularly targeted therapy for prostate cancer. Along the way, speakers also shed light on the disparities in cancer health care faced by minorities here in the United States and by people living in underdeveloped countries throughout the world.

The intersection of disparity and genetics

Olufunmilayo Olopade of the University of Chicago opened the symposium with a discussion of the roles of BRCA1 and -2 mutations in breast cancer in different populations, including white and black women in the United States and women from Nigeria—a population that is genetically linked to the U.S. through the historical slave trade. Olopade is examining the differences in these populations with the aim of reducing disparities and promoting research on new therapies to more effectively treat the cancer types found more often in black women.

Disparities in cancer outcomes exist in the U.S. and other countries.

Otis Brawley, chief medical officer of the American Cancer Society, synthesized a large body of research on cancer care disparities experienced by black Americans, relating these disparities to differences in socioeconomic status that prevent the adequate delivery and uptake of health care. His points were seconded and expanded upon by Franco Cavalli of the Oncology Institute of Southern Switzerland, who described worldwide disparities in cancer care that will exacerbate the epidemic of cancer predicted in the coming years. Cavalli's description of the need for cancer-control programs customized to the needs of each country echoed Olopade's contention that new treatments are needed that more closely fit the needs of black Americans.

The mechanisms of cancer metastasis were explored by Larry Norton of the Memorial Sloan-Kettering Cancer Center, Robert Weinberg of the Whitehead Institute and MIT, and Michael F. Clarke of the Stanford Institute for Stem Cell and Regenerative Medicine. Norton described his work on some mysterious properties of solid tumors, including distinctive growth kinetics and the recently recognized phenomenon that invasive cancer cells can return and re-seed the original tumor. His work suggests that these and other properties are a result of cancer cells' abilities to turn on complete programs of genes whose products give the cells the ability to travel through the body and to adapt to life in tissues far from where they originated.

New mechanisms and real world applications

Robert Weinberg described his work showing that metastatic cancer cells gain their abilities to invade and spread to distant tissues by turning on gene expression programs originally intended for use during development by embryonic stem cells. Clarke delved more specifically into the cancer stem cell hypothesis, describing his work on stem cell-like subpopulations of cells found in solid tumors. His research adds to the growing evidence that cancer stem cells use embryonic gene expression programs to promote both tumor growth and metastasis. The work of these three investigators has important implications for cancer therapy development because they suggest that targeting cell division, as most current therapies do, does not adequately target the cancer stem cells that pose the greatest danger to cancer patients.

Clarke's research on cancer stem cells also suggests that, like normal stem cells, these cells are relatively resistant to DNA damage. Jill Bargonetti of Hunter College described mutations in the p53 pathway that are often the source of this resistance. Cancer cells in which p53 function is disrupted are more resistant to cell death. Bargonetti's work aims to circumvent that resistance by finding anticancer agents that initiate p53-independent cell death pathways or that can restore normal p53 function.

Targeting cancer stem cells may be critical for preventing metastases.

The symposium arrived at the bedside with the work of Neil Bander of Weill-Cornell Medical College. Bander described clinical trials of a new targeted agent for treating prostate cancer that consists of a radioactive isotope or a toxin linked to a prostate-specific antibody. This new therapy is intended to treat existing metastatic disease as well as prevent progression to metastatic disease by seeking out and killing the many micrometastases spawned by the primary cancer. This strategy echoed the concerns of Weinberg—that the transition from micrometastasis to full blown metastatic tumor is perhaps the most dangerous event in cancer progression.

Midway through the symposium, a discussion panel formed by the first four speakers was tasked with giving advice to President Obama's new administration in the war on cancer. Perhaps predictably, the researchers agreed that more money for research should be an important component of the plan, although it would be difficult to fault this recommendation given the remarkable advances described in the course of the symposium. They also agreed that a more equitable distribution of cancer care, both at home and abroad, would go a long way toward alleviating cancer suffering and death, even in the absence of new scientific advances.

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen.

Olufunmilayo I. Olopade, University of Chicago


  • Both Nigerian and African-American women have a high proportion of cancers that are aggressive, basal-like, and estrogen receptor-negative, making these cancers more difficult to treat.
  • A relatively high proportion of Nigerian women carry mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, yet the majority of carriers have no family history of breast cancer.
  • The reduced penetrance of the BRCA mutations in Nigerian women may be related to environmental factors, including number of pregnancies or age of onset of menstruation, or to other genetic differences.
  • It is important to consider both genetic and environmental factors when counseling women with inherited cancer susceptibilities on their risk of cancer.

Genetics and cancer outcome

Cancer arises out of a complex interplay between genetic factors, including inherited and spontaneous mutations, and environmental factors, such as exposure to toxins or hormones. In breast cancer, an inherited susceptibility can be traced in many cases to mutations in the BRCA1 and -2 tumor suppressor genes. In the U.S., these mutations are thought to occur in somewhere between 1 in 150 and 1 in 800 women, and to account for 5%–10% of all breast cancers. However, these mutations are enriched in the gene pools of certain subpopulations—for example, among Ashkenazi Jews, where they occur in 1 in 50 women.

Olufunmilayo Olopade of the University of Chicago is studying the roles of these and other mutations in the development of breast cancer in African and African-American women. Epidemiologic studies show that African-American women experience much poorer outcomes from breast cancer than white women, a difference that has been attributed largely to disparities in health care access and delivery. But Olopade's research suggests that at least some of this difference can be attributed to underlying genetic differences in African-American women. She says the role of BRCA mutations in these women has been both "understudied and underappreciated," and suggests that a complete understanding of the role of these mutations in cancer development will only be achieved by more careful study of this and other underserved populations.

Olopade has begun to redress this imbalance by studying women with breast cancer in Nigeria, her country of origin and the origin of many of the slaves from whom today's African-Americans are descended. She and her group investigated clinical, genetic, and environmental characteristics in a group of 1095 breast cancer patients, compared to 1015 women without a history of cancer.

African sources of the slave trade.

Their studies showed a number of differences between breast cancer in Nigeria and the U.S. Although the overall incidence rate of breast cancer is lower in Nigeria, much of it is early onset. Early onset is a cardinal feature of genetically inherited cancers, suggesting that this population is enriched for a genetic predisposition. Breast cancer in this population tended to be more aggressive, with a higher proportion of cancers that were negative for over-expression of the estrogen receptor (ER). ER over-expression is the basis of many current therapies for breast cancer and thus ER-negative cancers are more difficult to treat. Breast cancer can be divided into a number of subtypes, such as luminal A, luminal B, and basal-like, based on histological and molecular characteristics. The Nigerian women had a lower proportion of the more easily treated luminal cancers, and higher proportion of the more aggressive basal-like cancers, which are usually associated with an ER-negative phenotype.

Less treatment, more aggressive cancers

These findings have important implications for our understanding of breast cancer in African-American women. It has been suggested that these women are diagnosed with more advanced cancers because their diagnoses are delayed due to lack of access to health care. While this factor may explain some of the discrepancy, it is also clear that breast cancers are more aggressive, growing faster and appearing earlier, in the populations from which these women derive their genetic heritage. In her own practice, Olopade has found that many African-American women are first diagnosed with very large, rapidly growing cancers, even when they are being screened at relatively short intervals due to a family history of cancer. Many current therapies are ineffective in these women because their tumors are often basal-like and ER-negative, suggesting that the development of new therapies for these types of tumors would also help address the disparity in outcomes. These factors need to be considered in health policy and research funding decisions, Olopade said.

78% of Nigerian women who tested positive for the BRCA mutations had no family history of breast cancer.

Olopade found another intriguing difference in the Nigerian population. Although she and her coworkers found a high prevalence of BRCA mutations, 78% of the women who carried these mutations had no family history of breast cancer. Geneticists call this phenomenon "reduced penetrance," that is, a mutation is present but its effects are somehow blunted by environmental factors or by the presence of other genetic differences.

Olopade and her coworkers are looking at both of these possibilities by studying environmental differences as well as differences in genes and proteins that are likely to play a role in the interaction of breast cells with their environment. In the latter category is an enzyme known as uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 is involved in estrogen metabolism, which is critical in breast development, and may also be involved in the detoxification of carcinogens. Certain variants of the gene for UGT1A1 are associated with 30%–50% reduced activity of the enzyme, and they have found that these variants are more prevalent in both African-Americans and Nigerians.

Environmental influences

They have also identified environmental factors that may play a role in reducing BRCA mutation penetrance, including differences associated with the number of pregnancies, duration of breast feeding, and age of onset of menstruation in these women. "Genes don't work in isolation," Olopade said, emphasizing the need to study all of the factors involved, including environmental factors and the potential role of epigenetic regulation.

Olopade's research reinforces the idea that the presence of a cancer-susceptibility mutation by itself does not predict the eventual outcome in a specific patient. It is important to understand the roles of these mutations in different ethnic and socioeconomic populations, potential reasons for differences in penetration in these groups, and other modifying characteristics when counseling women on their breast cancer risk. This type of information can only be gained by carrying out research in a variety of different populations, including those that are traditionally underserved. Olopade would like to add better research to the list, along with better health care access and better health care delivery, in the effort to improve outcomes for African-American women with breast cancer.

Franco Cavalli, Oncology Institute of Southern Switzerland


  • By 2030, the number of cancer deaths worldwide per year is predicted to nearly triple from 7.9 million in 2007 to around 20 million per year.
  • Developing countries are expected to be particularly hard hit by this increase due to their lack of preventative programs, access to cancer therapies, and other resources for fighting cancer.
  • Effective prevention and treatment strategies for cancer are highly dependent on cultural factors, local beliefs about cancer, and the types of cancer and cancer risks found in each country.
  • The International Union Against Cancer's World Cancer Declaration calls for the development of cancer control programs that are customized to the specific needs of each country.

The global cancer epidemic

Franco Cavalli of the Oncology Institute of Southern Switzerland expanded the themes of Olunfunmilayo Olopade and Otis Brawley to a more global scale. Cancer kills more people across the world than tuberculosis, AIDS, and malaria combined, he said, accounting for 7.9 million deaths in 2007. About 70% of these deaths occurred in low and middle-income countries. By 2030, the global cancer burden is predicted to reach around 20 million deaths per year, as a consequence of population growth and changes in demographics.

It is predicted that developing countries will be particularly hard hit by this increase due to increases in poverty-related tumors, tumors linked to adopting a Western lifestyle, a lack of preventative programs and therapies, and a lack of resources for treatment. Poverty-related tumors are those that occur due to a lack of screening or increased prevalence of infection in poorer populations. These include cervical cancer, which can be largely prevented by early detection; esophageal cancer, which is related to a poor diet and smoking; and liver cancer, which is related to hepatitis B virus infection.

30 countries in Africa and Asia have no radiotherapeutic equipment within their borders.

There is a worldwide shortfall in therapies for cancers that is particularly evident in developing countries. Radiation therapy is important in the treatment of many cancers, but 30 countries in Africa and Asia have no radiotherapeutic equipment at all within their borders. And although 61% of cancers occur in parts of the world outside the U.S., Japan, and Europe, only 5% of cancer drugs are sold there.

It has taken some time for this growing health crisis to be recognized. In 2005, the World Health Organization (WHO) decided to put cancer control on its global health agenda for the first time, and it is still the only worldwide organization that has done so. Cavalli is the immediate past president of the International Union Against Cancer (UICC), an umbrella organization of 322 cancer organizations in 102 countries that is pushing for increased global awareness of the cancer crisis. The UICC works to promote both the research and the political developments that are needed to result in the establishment of national cancer control plans in many different countries. They are also working to raise public awareness, leading to increased pressure on governments to do something to address this global health problem.

The UICC uses highly coordinated global efforts such as its World Cancer Campaigns, which are launched on World Cancer Day, February 4th, of every year. One such campaign is called "My Child Matters," and includes 26 catalytic childhood cancer projects in 16 countries. Pediatric cancer is one of the areas where the gap between developed and developing countries is the widest. Many pediatric cancers are cured at very high rates in developed countries but these same cancers are cured only 5%–10% of the time in developing countries.

Diverse cancer needs

Dissemination and adoption of prevention strategies is another important goal. Many cancer deaths are preventable, in fact, 43% could be prevented by stopping tobacco use, improving diet, and controlling infectious agents alone. In 2007, the UICC began a five-year cancer prevention campaign to address this need. The role of lifestyle elements such as smoking and diet varies among countries due to cultural differences, and an important aspect of these cultural differences is people's local beliefs about whether behavior plays a role in determining who will develop cancer. The initial thrust of this campaign has been the use of surveys to identify and understand cancer-related beliefs in 29 different countries. The results of these surveys will be used to develop interventions that are customized to the cultural background of each country.

Differences in the proportion of cancer deaths due to tobacco use, diet and infection between sub-Saharan Africa and Europe.

The role of infection in cancer risk varies by country as well. In sub-Saharan Africa, about 25% of cancers are caused by infection, compared with 6% in Europe. Infectious agents that can cause cancer include the human papilloma virus (HPV), which is responsible for cervical cancer and may be involved in head and neck cancers as well, and the hepatitis B virus that is a potential cause of liver cancer. Mortality from cervical cancer is very high in the developing world and much lower in the developed world, primarily due to better screening in wealthier countries. Another crucial difference in developing countries is a lack of data. For example, only 0.1% of the population of Africa is covered by some type of cancer registry, Cavalli said.

The UICC has incorporated many of these concepts into its World Cancer Declaration, which was adopted in 2006 as an urgent call for action on the cancer crisis. A revised version, adopted in Geneva in 2008, calls for the availability of cancer-control plans in all countries, substantial improvement in the measurement of cancer everywhere in the world, and substantial decreases in tobacco consumption, obesity, and alcohol intake. It also calls for universal vaccination in areas with high rates of HPV and hepatitis B infection, work aimed at dispelling local cancer myths, and improved access to screening, diagnosis, treatment, and palliative care worldwide.

The ultimate goal of the UICC's work is to encourage each country to adapt these basic goals to its own particular needs, creating a highly focused cancer control program with the potential to turn back the expected flood of cancer mortality in the coming years. "Prevention of cancer is a human right," said Cavalli, a statement that is reflected in the choice of Mary Robinson, former UN High Commissioner for Human Rights, as co-chair of the Cancer Leaders' Summit to be held in Geneva in August of 2009.

Larry Norton, Memorial Sloan-Kettering Cancer Center


  • Local control of breast cancer is important for preventing metastases but does not guarantee that they will not occur.
  • Breast cancer tumors have distinctive growth kinetics that may be explained by tumor re-seeding with cells that have traveled elsewhere in the body, and these kinetics have important implications for the timing of chemotherapy doses.
  • Tumor re-seeding may explain why local control of cancers sometimes fails unexpectedly.
  • Breast cancer cells may acquire the ability to invade tissues, form metastases and re-seed tumors by turning on gene expression programs originally intended for other purposes.

An invasive process

On the surface, the spread of metastatic breast cancer appears to occur by a very orderly process. If left untreated, abnormal cells form a localized cancer, known as a ductal carcinoma in situ, that breaks out of the milk duct and is carried through the lymphatic system to nearby lymph nodes called sentinel nodes. From there, cancerous cells can spread throughout the body to form metastases in other tissues and organs. This model of breast cancer metastasis was the basis on which William Stewart Halsted first proposed radical mastectomy as a cure for early breast cancer.

Radical mastectomy has since given way to lumpectomy for many women. But neither approach works 100% of the time. Some women whose cancers are caught early and removed before spreading to the lymph nodes still go on to experience life-threatening metastases. In addition, local irradiation of the breast in the area where a tumor has been found reduces the risk of distant recurrence even in women whose cancers appear to have been localized and fully removed.

Why doesn't local control of early breast cancer always work?

Why doesn't local control of early breast cancer always work, as this understanding of the process would imply? Larry Norton and his research group at Memorial Sloan-Kettering Cancer Center are investigating these and other mysteries of breast cancer in their effort to better understand the underlying mechanisms at work, with the ultimate aim of discovering new, more effective therapies to prevent metastasis and improve survival.

Norton described several other mysteries. Breast cancers appear in a number of well-characterized and somewhat diverse forms, in which certain characteristics tend to track together. Subtypes such as luminal or basal-like cancers can be identified by a cluster of histological, molecular, and clinical characteristics that lead to different treatment choices and differing prognoses. These characteristics can be related to underlying physiological processes. For example, the size of the tumor is related to the ratio between cell division and apoptosis in it, the histological grade is related to its underlying cellular architecture, and the amount of spread to the lymph nodes is related to the expression of factors that allow metastasis. For reasons unknown, changes in these three very different biological characteristics are always carried together in different histological subtypes of breast cancer.

Another mystery: recently developed genetic tests that profile gene expression in breast tumors can be used to gain valuable information about prognosis and the potential benefits from chemotherapy for the individual patient. But much recent work suggests that the cells that largely determine a tumor's characteristics are cancer stem cells, which are relatively rare within a tumor mass. How can a test be accurate if it is sampling from the large majority of tumor cells that are not cancer stem cells?

Finally, Norton described the growth kinetics of breast tumors, which follow a specific pattern known as a Gompertzian growth curve. The discovery of these kinetics has led to the finding that chemotherapy doses given close together in time are often more effective than the same doses given in a more spread-out fashion. This finding has held true in cancers as diverse as breast cancer and lymphoma. He and others have wondered what determines this distinctive pattern of growth.

Cancer cells can go home again

Norton and his coworkers have been working to shed some light on these mysteries by studying the characteristics of the tumors formed when cancer cells are injected into mice and allowed to grow and metastasize. They remove cells from the newly formed local tumors and the metastases, and examine their respective gene expression patterns. These studies have revealed unique genetic signatures for cells in the local tumor and in the metastases. Often the genes expressed correlate with the characteristics of the metastasis, for example, cells from fast-growing visceral metastases express growth-promoting genes, while metastases found in the lung overexpress genes related to the cells' need to make a new home in the lung environment.

Self-seeding may account for some of the growth characteristics of the tumor.

The ability of cancer cells to change their genetic programs to promote seeding of other areas of the body was not unexpected, and knowledge of the functions of these genes has the potential to lead to new therapies for preventing metastasis. But these studies have also revealed an unexpected finding: breast cancer cells that leave the original tumor can come back and re-seed it. Norton and colleague Joan Massague, also of Memorial Sloan-Kettering, have proposed that this property of self-seeding may account for some of the growth characteristics of the tumor that were previously attributed entirely to uncontrolled cell division and reduced cell death. Most current anticancer therapies target tumor growth by interfering with cell division. But if the high cell density and rapid growth rate found in tumors is due to the ability of their cells to move around the body and return, then therapies targeting genes and proteins involved in cell motility and invasiveness might be as effective or more effective than current therapies.

The ability of breast cancer cells to re-seed could also explain some of the mysteries outlined by Norton at the beginning of his talk. Re-seeding could explain Gompertzian growth kinetics because tumor growth would occur in a disorganized fashion from the outside in rather than the inside out. Re-seeding might also explain the need for radiotherapy after breast-conserving surgery that has apparently removed the entire tumor. The dispersal of cancer stem cells throughout the tumor by such seeding might also explain why genetic profiling works even though cancer stem cells are rare.

Norton and his colleagues are continuing to investigate the role of self-seeding in breast tumor growth and on properties such as the development of blood vessels, and tumor infiltration by leukocytes and other components of the immune system. They are also investigating the relationship between the level of tumor organization and prognosis in humans using MRI's of breast cancer tissue. Highly disorganized tumors may indicate a population of cancer cells that are particularly adept at re-seeding, and thus may predict a worse outcome for some patients. A better understanding of the molecular mechanisms underlying cancer cell self-seeding and mobilization to other parts of the body has the potential to reveal new drug targets, and may impact the future design of chemotherapeutic regimens using established drugs as well.

Jill Bargonetti, Hunter College


  • The transcription factor p53 plays a key role in regulating the cell cycle and entry into cell death pathways, particularly in the presence of DNA damage.
  • The functions of p53 are absent or weakened in many cancers, making cancer cells more difficult to kill with cytotoxic agents.
  • Cancer cells may also carry changes in MDM2, a negative feedback regulator of p53, which can also make them more difficult to kill.
  • New therapies that activate non-p53 cell death pathways or that restore p53 function may be more successful than current therapies at killing cancer cells.

Molecule of the year

In 1993, Science magazine named the tumor suppressor p53 it's "molecule of the year" in recognition of this transcription factor's central role in cancer. The p53 protein lies at the center of a critical regulatory pathway that is essential for normal cell growth and death as well as for cell recovery from DNA mutations and damage. Over 50% of cancers carry a mutation in the gene for p53, and in many cancers where it is not mutated, the p53 protein is inactivated by other mechanisms.

The p53 protein is a 53 kilodalton phosphoprotein that is found in the cell nucleus and functions as a transcription factor. Researchers investigating the role of p53 in cancer soon discovered that not all cancers carry the same p53 mutation. The central core domain of the protein, which is responsible for binding to specific DNA sequences, is the hotspot for cancer-producing mutations. In addition, the activity of p53 is negatively regulated by another protein known as MDM2, which is itself a frequent site of cancer-producing mutations.

Can p53 be reactivated in cancer cells?

Jill Bargonetti and her group at Hunter College are exploring the implications of the diverse ways in which p53 function can be disrupted in cancer cells. In particular, they are investigating whether parameters describing the p53 status of cancer cells, such as the expression levels of p53 or MDM2, or the presence of specific mutations in these proteins, can be used as biomarkers to aid the development of new cancer therapies. In other words, they are using a pharmacogenomic approach that takes the underlying genetic differences between cancers into account when exploring and testing ideas for new therapies. These considerations have led them to test new strategies for killing cancer cells that involve inducing cell death by p53-independent pathways, or reactivating p53 so that it can play its normal role in initiating the cell death process known as apoptosis.

Bargonetti and her group are using two breast cancer cell lines, one of which carries wild-type p53 and the other mutant p53. Cancer cells lacking normal p53 function are harder to kill because they are deficient in their ability to enter normal death pathways. Some anticancer agents, including etoposide, are already known to kill cells by p53-independent pathways, but not very efficiently. Bargonetti and her group are looking for new agents that kill cancer cells in the absence of a functioning p53 by identifying compounds that kill both breast cancer cell lines with equal efficiency. Preliminary results suggest that one such agent is 8-aminoadenosine, which appears to activate p53-independent cell death pathways.

A protective function

Some cancer cells produce high levels of inactive mutant p53, and Bargonetti and her group have discovered that these high levels of expression can confer a survival advantage. They have found that using viral or shRNA targeting to reduce the expression of p53 in their mutant p53 breast cancer cell line sensitizes these cells to stress-induced damage. Thus knockdown of mutant p53 expression could be used to sensitize breast cancer cells to damage inflicted by other anticancer agents. Bargonetti and her group plan to test combinations of such therapies to see if this strategy increases their effectiveness.

Estrogen promotes MDM2 expression, possibly providing a mechanism for hormonal effects in certain forms of cancer.

Mutations that increase the expression of MDM2 can also be oncogenic because the increased levels of MDM2 inhibit normal p53 function and thus prevent the cell from entering normal cell death pathways. The hormone estrogen also promotes MDM2 expression, possibly providing a mechanism for the role played by hormones and gender in certain forms of cancer. Many groups are targeting the interaction between MDM2 and p53 as an attractive way to promote the killing of cancerous cells.

Bargonetti and her group are studying a human single nucleotide polymorphism in MDM2, known as SNP309, that causes MDM2 overexpression and is associated with the earlier onset of cancer. They are investigating the mechanism by which MDM2 overexpression inhibits p53 function in cultured cancer cell lines, with an eye toward developing better therapies for hormone-dependent cancers such as estrogen receptor-positive breast cancers. Their experiments suggest that using gene silencing to reduce MDM2 levels in breast cancer cells with wild-type p53 could reactivate p53 that was previously inhibited, thus increasing the chances of killing the cell with cytotoxic therapies.

Bargonetti's studies strongly suggest that future, personalized treatment of cancer will need to include knowledge of underlying mutations in p53 or MDM2 when they are present. Strategies that activate p53-independent cell death pathways or that reduce the expression of mutant p53 or wild type MDM2 are likely to be valuable in developing new therapies or as a means to enhance the activity of currently available anticancer agents.

Michael F. Clarke, Stanford Institute for Stem Cell and Regenerative Medicine


  • Many tumors can be separated into at least two populations of cells: cancer stem cells that can give rise to new tumors, and non-tumorigenic cells that cannot.
  • Cancer stem cells share a number of properties with normal tissue stem cells, including the ability to both differentiate and self renew and the expression of genes that are involved in these processes.
  • Like normal stem cells, cancer stem cells are resistant to DNA damage by radiation, a property that may have important implications for the development of new therapies.

Cancer stem cells: the evil twin

Michael Clarke of the Stanford Institute for Stem Cell and Regenerative Medicine provided some background on normal stem cells before explaining his studies of cancer stem cells and their roles in cancer development. Clarke pointed out that cancers tend to occur in tissues that continually regenerate, such as the skin, the lining of the gut, or the blood. Blood cells in particular must be replenished constantly. Blood contains a complex mixture of myeloid and lymphoid cells with varying life spans, differentiation patterns, and abilities to self renew, thus necessitating the existence of stem cells that can maintain these distinct cell populations as well as replenish themselves as needed.

Like blood, many tumors are composed of heterogeneous mixtures of cells that are in different states of differentiation. This observation has given rise to two models for cancer heterogeneity. According to the stochastic model, all of the cells in a tumor are capable of giving rise to the phenotypically heterogeneous cells found there. According to the stem cell model, only the cancer stem cells in the tumor can give rise to other cell types. In the stem cell model, the other cells in the tumor proliferate on a more limited basis, and only give rise to cells of their same type.

Models for heterogeneity in tumors.

Clarke and his group are investigating the properties of tumor cells by introducing specific populations of cells derived from human breast, colon, and head and neck cancers into mice and studying their ability to form new tumors and metastasize. Using these model systems, Clarke and others have been able to identify phenotypically different cells in solid tumors that have the exclusive ability to give rise to new tumors, which they have identified as cancer stem cells. They have found that the bulk of the cells in most tumors are non-tumorigenic, that is, they are not capable of self renewal and thus cannot form new tumors.

A capacity for self-renewal

Clarke and his group are working to characterize these putative cancer stem cells in order to confirm their identity. The stem cell hypothesis makes some predictions about what cancer stem cells should look like. First, it suggests that there should be similarities between cancer stem cells and normal tissue stem cells, and these similarities should be manifested as similarities in gene expression patterns. Clarke and his group have found that head and neck cancer cells growing near the outside of a tumor do in fact express normal stem cell markers, while non-tumorigenic cells inside the tumor express markers for mature differentiation. They have also found that breast cancer stem cells overexpress normal mammary stem cell genes.

Changes in Bmi-1 could have effects on cancer stem cell self-renewal.

The stem cell hypothesis suggests that cancer stem cells should be self-renewing, while the non-tumorigenic cells in the cancer should lack this capacity. Clarke and his group have found that cells identified as breast cancer stem cells overexpress genes associated with self-renewal compared to non-tumorigenic cells in the same tumor. In cancers like chronic myeloid leukemia, where there is a large increase in the number of cells capable of self-renewal, they have identified a number of genes whose expression is required for self-renewal. This includes genes such as Bmi-1, an epigenetic regulator that is part of the Polycomb family of genes involved in embryogenesis. Simultaneous mutation of three of the downstream targets of Bmi-1 leads to a 12-fold increase in stem cell activity in normal mouse bone marrow, suggesting that changes in this gene could have effects on cancer stem cell self-renewal as well. Some of the same self-renewal associated genes that they identified in leukemia are overexpressed in breast cancer stem cells as well. These observations support the hypothesis that there is a specific population of cells within tumors whose ability to self-renew is enhanced by the expression of specific genetic programs that are also used in normal stem cells.

Other important characteristics of normal stem cells include their innate resistance to apoptosis, toxins, and DNA damage, properties that help them survive catastrophic events to repair the organism if needed. Clarke and his group have shown that cancer stem cells are resistant to radiation-induced DNA damage, and that human breast cancer stem cells overexpress genes for proteins involved in radioprotection. Cancer stem cells might also be innately resistant to chemotherapies, which usually act by cytotoxic mechanisms such as the induction of DNA damage. These findings may explain why current cytotoxic approaches to cancer tend not to be very successful, since they would be less likely to kill cancer stem cells. They also reinforce the idea that discovering drugs that are toxic to cancer stem cells may provide a new and better approach to successfully treating cancer.

Neil H. Bander, Weill Medical College of Cornell University


  • The J591 antibody specifically binds to a cell-surface protein present only on prostate cancer cells.
  • J591 is being developed as an agent that can target and deliver radioisotopes or toxins specifically to prostate cancer cells without affecting normal cells.
  • This property could allow selective destruction of prostate cancer micrometastases, which are carried by about 750,000 men in the U.S. who have failed initial treatment.
  • Phase I and II studies have shown that the antibody-isotope and antibody-toxin conjugates are well-tolerated and have anti-tumor activity in a significant proportion of men whose cancer has already metastasized.
  • Studies that will soon start in men with less advanced disease will show if this strategy is capable of preventing the occurrence of life-threatening metastases.

A targeted approach

Neil Bander of the Weill Medical College of Cornell University brought the symposium to the bedside for the last talk, describing his group's work developing immunological agents that target prostate cancer. Prostate cancer is an ideal candidate for an immunologically-based approach because it tends to metastasize to the bone marrow and lymph nodes, where the cancer cells are readily accessible to high levels of circulating antibodies. The approach is also aided by the ability to identify prostate cancer patients who are at high risk for metastasis very early on, when they harbor only micrometastases. The very low tumor burden in these patients improves the likelihood of success.

Prostate cancer is also a good target for therapies that prevent metastases. There is a large population of prostate cancer patients for whom surgery or radiotherapy has failed, representing about 750,000 men in the U.S., and most of these men harbor micrometastases. This population is readily identified, carries a low disease volume, and has undergone minimal pre-treatment, all factors that present a favorable setting for potentially curative therapy.

Increased PSMA expression correlates with more aggressive tumors.

Bander and his group have developed an antibody called J591, which targets a membrane-bound protein known as the "prostate-specific membrane antigen," or PSMA. Expression of this protein is restricted to the prostate, and virtually all prostate cancers are positive for it. Increased PSMA expression correlates with biologically more aggressive tumors, and the hormonal therapy often given for prostate cancer also upregulates its expression.

PMSA is found on the cell surface of prostate cancer cells, making it a good candidate for an antibody-based therapy that depends on initial binding to the outside of the cell. PMSA is also internalized by the cell, which means that it can carry an antibody with an attached toxin into the prostate cancer cell for very specific cell killing, in what is known as a "payload" approach. The discovery of PMSA internalization was a serendipitous one, since the protein did not carry any previously identified signaling motifs for internalization, although Bander and his group have since identified a novel internalization motif.

The killer payload

The J591 antibody is designed to be used as a targeting agent that directs toxic agents specifically to prostate cancer cells. Bander and his group have thus far tested three options for the toxic portion of the molecule: two radioisotopes, yttrium-90 (90Y) and lutetium-177 (177Lu), and a cytotoxin known as DM1. The radioisotope approach was chosen to take advantage of the relative sensitivity of prostate cancer cells to radiation. These particular isotopes were chosen because the physical characteristics of the radiation that they emit can be well matched to the size of prostate cancer metastases.

Since their development, the various antibody payloads have been the subject of 11 clinical trials in over 300 patients. Phase I studies for safety showed that these agents are well tolerated, are highly specific in their ability to target prostate cancer cells, and show significant biological activity. Doses of the J591-isotope payloads are ultimately limited due to the development of thrombocytopenia, or low platelet counts, a common side effect of radioisotope therapies due to their effect on the bone marrow.

The 177Lu-antibody conjugate was advanced to phase II trials in men with progressive, metastatic prostate cancer who were not responding to hormone therapy, or, in a majority of patients, to chemotherapy even though this isotope is more ideal for patients with micrometastases rather than the more extensive metastatic disease found in this patient population.The recently completed trial showed that the 177Lu-antibody was very specifically directed to prostate cancer metastases but not to normal tissues. Successful tumor targeting was seen in 30 of 32 patients. Approximately 2/3 of patients showed a drop in blood levels of prostate specific antigen (PSA), which is a measure tumor burden. Overall, the new agent showed significant anti-tumor activity in a patient population that was less than ideal due to the high burden of disease and prior chemotherapy received by many of the patients.

Localization of J591 antibody-radioisotope in a prostate cancer patient.

Bander and his coworkers hope to improve the efficacy of this therapy by administering multiple doses of the antibody-conjugate, and by using recently FDA–approved agents that promote platelet production in order to overcome the dose limitations imposed by thrombocytopenia in some patients. They are also testing their new therapy in combination with the chemotherapeutic drug docetaxel (Taxotere, Sanofi Aventis), an antimicrotubule agent that has been shown to improve survival rates in men with metastatic prostate cancer. Docetaxel acts as a radio-sensitizer, so it may promote the cell killing action of the conjugated radioisotope. They have also received approval to start a large, multicenter, randomized phase II trial in men with progressive but non-metastatic disease. This population will be more appropriate for the 177Lu isotope, which works best in 1 to 3 millimeter prostate cancer micrometastases. This new therapy appears to have the potential to greatly improve prostate cancer survival rates in the coming years.

Will the development of new therapies for estrogen-receptor negative breast cancer improve survival rates in African-American women?

Will cancer survival rates be improved for minorities and those of lower socioeconomic status by a more equitable distribution of health care resources in the future?

Will developing countries be able to develop cancer-control plans in time to stem the expected increase in cancer-related deaths?

How will the concept of tumor re-seeding affect the future development of anticancer therapies?

Will it be possible to design therapies that target cancer stem cells without deleterious effects on the normal stem cells needed for tissue regeneration?

Would targeting cancer stem cells alone be sufficient to kill most cancers or must the non-tumorigenic cells be targeted as well?

Will it be possible to develop an agent that restores p53 function in humans as a means of enhancing current cancer therapies?

Will the J591 antibody-radioisotope conjugate prove effective at killing micrometastases of prostate cancer before they have a chance to form dangerous metastatic tumors?

Otis W. Brawley, American Cancer Society, Emory University


  • Black women have a higher risk of death from breast cancer than white women in the United States.
  • Studies in Scotland, where genetic diversity is relatively low, have shown that cancer survival is closely tied to socioeconomic status.
  • Both black women and women of lower socioeconomic status are diagnosed at younger ages with cancers that are more aggressive, more likely to be estrogen-receptor negative, and more difficult to treat.
  • Black women who receive the same care for the same type of breast cancer have outcomes that are equivalent to those of white women.
  • Much of the disparity in breast cancer survival could be alleviated by ensuring that all women have equal access to health care regardless of race or socioeconomic status.

A question of access

As chief medical officer of the American Cancer Society, Otis Brawley of Emory University is well acquainted with the health care disparities facing African-American women with breast cancer. As he began, Brawley noted that he does not disagree with Dr. Olopade's findings that some of these discrepancies might be due to differences in underlying genetics. However, the main thrust of his talk was that black women who receive the same level of care for breast cancer often have outcomes that are just as good as for white women, reinforcing the need to ensure that health care is delivered equally to all populations.

Some of the discrepancy in cancer outcomes could be alleviated by improved access to health care.

In his talk, Brawley synthesized much of the current research on treatment patterns in breast cancer as they relate to underserved populations. He began by contrasting breast cancer statistics from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program, which covers the general population, with those of the Department of Defense, which covers only those in the military. In both cases, blacks had higher breast cancer mortality than whites. But black women in the armed forces have lower mortality than black women in the general population. As members of the military, these women have greater access to health care, suggesting that at least some of the discrepancy in the overall population could be alleviated by improved access to health care.

Brawley noted that health care is not delivered optimally even among women who already have good access. About 59% of breast cancers are now detected by mammogram, and as might be expected, uninsured, poorly educated women have very low rates of receiving this screening test. But statistics show that even insured women with a very high level of education have mammograms at a rate of only a little over 60%.

Access and affluence

In addition to differences in screening, studies have shown that breast cancer survival is lower among uninsured women, and their stage at diagnosis tends to be higher. Lack of health insurance is a socioeconomic factor, and Brawley explored the relationship between socioeconomic status and outcomes from cancer by discussing studies performed in Scotland. These studies use a "deprivation index" that measures socioeconomic status by tallying such factors as income and unemployment levels, housing density, and possession of a car and indoor plumbing. The studies have shown that people on the more affluent end of this scale have better survival rates of six types of cancer, including breast and colon. Since there are few black people living in Scotland, these studies serve to isolate the role of socioeconomic status from race in cancer outcomes, and suggest that access to health care is a problem in the absence of genetic differences caused by race or ethnic origin.

Brawley presented further studies suggesting that lower socioeconomic status and the resulting reduced access to health care play an important role in the poor outcomes experienced by many black women. Statistics from SEER show that at the time of breast cancer diagnosis, black women tend to be younger, have more advanced disease with higher grade tumors within the stage at which they are diagnosed, and have fewer ER-positive tumors. Other studies have shown that white women with lower socioeconomic status present with almost the same characteristics at diagnosis.

Researchers have gone on to investigate the reasons behind the link between socioeconomic status and breast cancer outcome. Obesity, as measured by a high body mass index (BMI), is known to raise the risk of breast cancer death, and obesity is more prevalent among black women. Several studies have suggested a correlation between higher BMI and higher stage at diagnosis of breast cancer. Obesity is both an economic and cultural phenomenon, Brawley noted.

Trends in female breast cancer death rates by race and ethnicity in the U.S., 1975 to 2004.

Other factors that may play a role include differing birthing patterns, since women of higher socioeconomic status tend to give birth later, and differing use of hormone replacement therapy in menopause, which is related to economic and insurance status. These differences, which may result in different levels of exposure to estrogen, may explain another phenomenon, which is that white women have a much higher prevalence of ER-positive cancers than black women. The higher incidence of ER-positive breast cancer in white women is the main reason why white women have a higher overall incidence of breast cancer than black women. ER-positive breast cancer is more easily treated than ER-negative, which may explain why white women have better survival rates in the face of this higher incidence. The two groups have a similar incidence of ER-negative breast cancer.

Equal treatment, equal outcomes

Brawley also presented research that demonstrates that both blacks and poor people receive poorer care for cancer, including delayed treatment, inappropriate treatment such as lack of adjuvant therapy, surgery, or radiation when needed, and dose reductions in chemotherapy regimens. Studies have shown that quality of care has an important impact on outcomes in breast cancer. For example, women who receive greater than 85% of the planned dose of adjuvant chemotherapy after mastectomy have a five-year relapse-free survival rate of 77%, compared to 48% in those who receive less than 65% of the planned dose. SEER data shows that both blacks and Hispanics are less likely to receive the minimum expected care for cancer. About 7.5% of black women with localized breast cancer do not receive surgery to remove the tumor, compared to 2% of white women. All of the women represented by these statistics were diagnosed with breast cancer, which suggests that health care disparities exist beyond access to appropriate screening and diagnosis.

Health care disparities exist beyond access to appropriate screening and diagnosis.

Brawley suggested that "equal treatment leads to equal outcomes," and presented data from several studies to support this statement. A very recent study showed that there were no racial differences in survival once data had been adjusted for mammography screening, tumor characteristics, the presence of biological markers such as the estrogen receptor, treatment given, co-morbid conditions, and other demographic characteristics. These findings may represent the intersection between socioeconomic and genetic considerations. Equal outcomes were obtained when the tumors had the same histological and molecular characteristics. Olopade's research, and some of the results presented by Brawley, show that black women do not necessarily develop the same types of tumors as white women and this may be the source of some of the discrepancies in outcome.

In many cases, getting good care for cancer is a "logistical issue," Brawley said. People of lower socioeconomic status often lack readily accessible transportation to treatment sessions, or may have the types of jobs that preclude daily chemotherapy or radiotherapy sessions. Cultural differences may lead to good therapy being refused, and disparities in co-morbid conditions may prevent the use of aggressive therapies in some blacks. Racism and discrimination may lead to good therapy not being offered. Brawley's conclusion is that "simply getting good care to blacks and the poor will improve overall American breast cancer statistics."