BETHESDA, MarylandDuring the past 18 months, researchers have developed substantial evidence supporting the notion that stem cells play a critical role in the development of at least some cancers, their progression, and the prognosis of patients, including breast, brain, lung, and prostate cancer, multiple myeloma, and melanoma.
"The idea of stem cells in cancer is a very old one, but it is only recently that scientists have had experimental models that actually validate this," Max Wicha, MD, professor of internal medicine and director of the University of Michigan Comprehensive Cancer Center, Ann Arbor, said at a meeting of the National Cancer Advisory Board (NCAB). "It represents a paradigm shift in how we need to approach cancer because it has very wide clinical implications."
The stem cell hypothesis challenges the classic stochastic model, which holds that cancer results from a random mutation in a cell that reproduces and eventually forms a malignant neoplasm. In contrast, the stem cell model suggests that in many instances, stem cells or their immediate progeny are the cells transformed during carcinogenesis, and that only these cells are capable of self-replication within a tumor. All other cells in a cancer have lost their ability to self-renew and are in various stages of differentiation.
Moreover, if these differentiated cells should escape the primary tumor and travel to other parts of the body, they would not grow metastases of clinical consequence. This means that once a cancer develops, its growth is driven by a small number of cellsperhaps as few as 100which have the two distinguishing properties of stem cells, namely the ability to make exact copies of themselves and to differentiate.
In the Michigan team's scenario, a stem cell that reaches a distant site might settle in a microenvironment that fails to support its immediate proliferation. This could explain the dormancy of tumors and their late emergence when the environment becomes right to put the cell back into cycle.
"If the stem cell model is correct, then we have to reexamine, in a very critical way, the preclinical models for therapeutic development," Dr. Wicha said. "We have to look at the endpoints for clinical trials, which may not be adequate because the tumor stem cells may be resistant to these therapies. And we think effective therapies will need to target the tumor stem cell population while sparing normal stem cells. Our laboratory and others are working on potential strategies to target this cancer stem cell population." Dr. Wicha is one of the founders of OncoMed Pharmaceuticals, a California-based biotech company that is developing technology to target cancer stem cells.
Five years ago, Canadian scientists suggested that stem cells were key players in leukemia. Dr. Wicha, working with Michael F. Clarke, MD, now at the Stanford University Comprehensive Cancer Center, began investigating the role of stem cells in breast cancer.