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Point of View : May 1, 2008 ( )
Cancer Stem Cells: Fact or Fiction
Many Issues Still Must Be Addressed before Betting the Farm on CSCs
GlaxoSmithKline (GSK) inked a $1.4 billion deal with OncoMed to eliminate cancer stem cells (CSCs) with mAbs, an investment based on the belief that cancer stem cells are the source of all solid tumors. Scott Kern, M.D., an expert on pancreatic cancers from the Johns Hopkins University, however, disputes the very existence of CSCs and argues that a belief in them is more akin to religion than science. In stark contrast, Robert Weinberg, Ph.D., professor of biology at MIT, says that CSCs are “mind blowing” and that “the entire mindset of people must now be refocused onto these stem cells.” He further argues that wiping out cancer stem cells will cure the disease.
Given such radically divergent opinions, one should ask: What are the clinical facts? Let’s start with, what are CSCs? According to Dr. Weinberg, “A cancer stem cell is defined as a cell that when plucked out of the tumor and introduced into a new host like a mouse is able to spawn an entirely new tumor.” Thus, when human cells are taken from resected cancerous tissue and transplanted into immunocompromised mice, only a small percentage of such cells seed new solid tumors.
One viewpoint is that these tumors are initiated by stem cells that have become abnormal through mutations or derive from cells that have reacquired embryonic gene-expression programs via mutations and returned to a stem-cell state. A critical requirement for true believers is to demonstrate in patients that tumors derive from bona fide stem cells. If this essential condition is not met, then we are left with little more than cancer-initiating cells (CICs) defined by growth in a mouse. They have the aura of stemness but not the substance.
Existing data reveals that the majority of samples taken from head and neck tumors of patients do not seed new growths in mice. Therefore some tumors contain neither cancer stem cells nor cancer-initiating cells. Furthermore, the cytogenetic data from transplants reveals cells with abnormal genomes having losses or gains of whole chromosomes or parts of chromosomes (aneuploid and segmentally aneuploid cells) and transplants from different patients exhibit different abnormal genomes; no two genomes are the same.
This raises some questions. Are the cells defined by mouse transplantation the same cells that leave the primary tumor, metastasize, and cause the death of the patient, or are they simply the survivors in immunocompromised mice? Are the dangerous cells that disseminate and metastasize in patients derived from bona fide stem cells embedded in different tissues or derived more simply from differentiated cells within a tumor? Does drug resistance after chemotherapy result from an inherent property of CSCs or from selection on a genomically heterogeneous nonstem-cell population challenged with drugs?
The fourth example involves cervical cancer data, which is especially informative because early precancerous abnormalities are available for examination from hundreds of millions of PAP smears. No other cancer can be detected so readily at its inception, since most cancers such as brain, breast, and prostate remain inaccessible to viewing in the earliest stages.
How then does such clinical and experimental data benefit cancer patients? Unfortunately, despite the hype and the aggressive marketing, there are no therapeutic benefits in the short term. The oncologist’s immediate concern is to help patients live longer and feel as good as possible during treatment. Thus, the primary tumor is resected or treated with radiation, and if cells have not disseminated, then the patient is fully cured. Since the extent of dissemination is generally unknown at the time of surgery, conventional radiotherapy, chemotherapy, and new drug treatments inexorably follow.
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