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The stem cell theory of cancer proposes that a relatively small number of rare stem cells drive tumor formation and progression. The majority of cancer cells, cancer stem cell (CSC) theory advocates say, can’t sustain the tumor nor establish it elsewhere in the body; only CSCs are tumorigenic and have a metastatic phenotype. The CSC theory has significant implications for cancer research and therapy and may explain why treatments focused on reducing tumor mass by removing proliferating cells fail to eliminate tumors.
Or maybe not. Despite a large number of publications supporting the existence of stem cells in tumors including human blood-cell derived cancers and solid tumors of the brain, breast, colon, pancreas, prostate, and skin, the issue of CSCs remains in serious contention.
“The major problem with the cancer stem cell idea is that it is not supported by data—neither clinical observations nor basic science,” according to Kornelia Polyak, M.D., Ph.D., a Dana-Farber researcher who studies the origin and progression of breast cancer. She and several colleagues say the model provides a simplistic and probably erroneous explanation for cancer recurrences and offers false hope of a silver bullet for many types of cancer.
Other Dana Farber scientists, however, hold a different view. “What's nice about the cancer stem cell hypothesis is it explains a lot of things, especially in the area of brain cancer, where I work, such as how you get brain cancer in the first place,” said Charles Stiles, Ph.D., co-chair of Dana-Farber's department of cancer biology. “A highly malignant cell with stem-like properties could account for the bizarre collection of different cell types found within the most deadly brain cancer, glioblastoma multiforme.”
The Ongoing CSC Debate
The existence of stem cells in tumors has been invoked to explain why some cancers keep going, no matter what chemotherapies or immunotherapies are used. Stem cells usually cycle slowly and thus are relatively insensitive to treatments aimed at stopping cell replication.
CSCs are more resistant to conventional cancer drugs not only due to quiescence relative to cancer cells but also because they are characterized by increased expression of antiapoptotic proteins and drug efflux transports. Additionally, according to recent findings, they rapidly change antigen expression, making them unlikely targets for immunotherapies that target cell surface proteins.
According to the NCI, the CSC theory states these cells are biologically distinct from the other cells that form the bulk of a tumor in that they can self-perpetuate and produce progenitor cells, like normal stem cells. The CSC progenitor cells then repopulate tumor cells eradicated by treatments.
The NCI concedes, though, that for all the attention CSC research has received, the findings reported to date are far from clear-cut, something many investigators freely acknowledge. For example, most studies that have identified human CSCs have used mouse xenograft assays, with cells from only a small number of human tumor samples. Researchers have also had problems replicating initially reported findings.
“I think that there are some cancers that do clearly follow a cancer stem cell model, but it will be more complicated than what’s been presented so far,” said Sean Morrison, Ph.D., who directs the Center for Stem Cell Biology at the University of Michigan (U-M).
Those in Favor
A close look at the literature indicates that the CSC model rests on firm experimental foundations, stated Robert Weinberg of MIT’s Broad Institute. He and his colleagues noted that the differences in the observed frequencies of CSCs within tumors reflect the various cancer types and hosts used to assay these cells.
Studies of stem cells and the differentiation program termed the epithelial-mesenchymal transition (EMT) point to the possible existence of plasticity between stem cells and their more differentiated derivatives. If present, such plasticity would have major implications for the CSC model and for future therapeutic approaches.
Some theories of cancer development say that some cells within the primary tumor reactivate EMT and that the mesenchymal traits acquired by transformed epithelial cells seem to facilitate metastasis.
Accumulating evidence suggests that EMT and mesenchymal-related gene expression are associated with aggressive breast cancer subtypes and poor clinical outcome in breast cancer patients. More recently, the EMT program was shown to endow normal and transformed mammary epithelial cells with stem cell properties including the ability to self-renew and efficiently initiate tumors.
In spite of research backing the CSC theory, there are many who believe that the stem cell model has not been adequately tested in most cancers. In January 2008, investigators identified a subpopulation enriched for human malignant melanoma-initiating cells defined by expression of the chemoresistance mediator ABCB5. Details reported in Nature by scientists from the Transplantation Research Center of Children's Hospital Boston and Brigham and Women's Hospital suggest that specific targeting of this tumorigenic minority population inhibits tumor growth.
ABCB5+ tumor cells detected in human melanoma patients showed a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possessed greater tumorigenic capacity than ABCB5-bulk populations and re-establish clinical tumor heterogeneity.
Additionally, Dr. Morrison and his team published a paper in the December 2008 issue of Nature showing that use of a standard immunodeficient mouse model, the NOD/SCID mouse, underestimates the frequency of tumorigenic human cancer cells. They showed that modified xenotransplantation assay conditions including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (IL2Rα<super>null</super>) mice can increase the detection of tumorigenic melanoma cells by several orders of magnitude.
Exemplifying the debate are the findings, published last June, of scientists at Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine that a population of human melanoma cells developed into tumors in immunodeficient mice. The isolated cells originated at various sites and stages and were enriched for expression of the CD271+ bearing cells.
The CD271+ subset of cells was the tumor-initiating population in 90% of melanomas tested in the study, according to the researchers. However, melanoma did not develop after transplantation of isolated CD271- cells. The investigators also showed that tumors derived from these MTSC CD271+ transplanted human melanoma cells could metastasize in vivo.
Additionally, the CD271+ melanoma cells were found to lack expression of TYR, MART1, and MAGE in 86%, 69%, and 68% of melanoma patients, respectively. This helps to explain, according to the investigators, why T-cell therapies directed at these antigens usually result in only temporary tumor shrinkage.
Hierarchy for Tumorigenic Potential
In commenting on this research, Peter Dirks of Toronto’s Hospital for Sick Children said, “Among the variety of cancer-cell subpopulations that make up a tumor, it is thought that only a select few—cancer stem cells—can drive tumor formation. Whether there is a hierarchy for tumorigenic potential among cancer cells, or whether every cell in the tumor has the same capabilities, is not yet certain.”
Dr. Morrison’s team reported details, in the November 18 edition of Cancer Cell, of their study to assess whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and nontumorigenic cells or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. They found that most types of melanoma cells can form malignant tumors, providing new evidence that this form of cancer does not conform to the CSC model.
The scientists observed that 28% of single melanoma cells obtained directly from patients in their study formed tumors in NOD/SCID IL2Rα<super>null</super> mice, the same model used in the 2008 paper cited above. All stage II, III, and IV melanomas had common tumorigenic cells. They appeared to have unlimited tumorigenic capacity on serial transplantation, exhibited phenotypic diversity, and their phenotypic differences were not hierarchically organized in terms of tumorigencity.
“They're phenotypically different from each other not because they're hierarchically organized but because they're just turning these surface markers on and off,” according to Dr. Morrison.
The U-M team found that all tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns and that all of those subpopulations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to nontumor-forming states, as the CSC model would predict.
To Target CSCs or Not
At stake in all this is how drug development to treat malignant melanoma may play out. Dr. Morrison told GEN, “Our findings suggest it will not be possible to cure patients with melanoma by targeting rare subpopulations of cells and that therapies should attempt to eliminate as many cells as possible. We are not able to find any melanoma cells that lack the potential to contribute to disease.”
In a 2008 paper published in Pigment Cell Melanoma Research, investigators said, “We propose that a subset of malignant melanoma stem cells may be responsible for melanoma therapy resistance, tumor invasiveness, and neoplastic progression and that targeted abrogation of a metastatic melanoma stem cell compartment could therefore ultimately lead to stable remissions and perhaps cures of metastatic melanoma.”
Dr. Morrison, on the other hand, proposes that pretty much all melanoma cells can originate and propagate the malignancy. “The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability.
“We believe that it won't be possible to cure patients by targeting rare subpopulations of cells,” Dr. Morrison concluded. “We think you need to kill all the cells.”