The publication of the landmark paper by Al-Hajj et al, which demonstrated that breast cancer cells capable of tumor outgrowth when transplanted into the cleared mammary fatpad of immunocompromised mice could be prospectively identified using cell surface markers, galvanized the cancer stem cell debate among breast cancer researchers and launched an exponential increase in papers exploring “breast cancer stem cells.” In this issue of ONCOLOGY, Federici et al review this explosion of literature in a clear and concise article that, like all broad reviews of rapidly expanding, highly debated fields, is greatly constrained by the need for brevity.
The dramatic discourse that was launched by Al-Hajj’s work, which suggested that solid tumors such as breast cancer could be completely recapitulated by only a small fraction of the tumor cells, was initially dominated by the stem cell purists’ demand for clear and rigorous definitions of cancer stem cells. Ideally, in every report, each system, surrogate, tissue, or cell line studied was to be interrogated for the hallmarks of cancer stem cells: self-renewal, multipotency, and quiescence. Inevitably, however, the demonstration, in a small number of reports adhering to these standards, that markers and culture techniques can identify or enrich for self-renewing “cancer stem cells,”[2, 3] has led to surrogates, such as those described by Federici et al—eg, mammosphere formation or aldehyde dehydrogenase activity—being equated to cancer stem cells in the absence of functional studies to complement this work. In addition, properties well studied in normal hematopoietic stem cell biology and in hematologic cancer stem cell biology have been assumed to be relevant to solid tumor stem cells, in many cases in the absence of comparable solid tumor data. Thus, perhaps the greatest omissions in the breast cancer stem cell reviews to date, including those by this author (WAW) have been the failure to separate the rigorous work incorporating functional cancer stem cell assays from those relying primarily on marker studies, and the failure to fairly reflect the limitations and complexities of the current literature.
It is clear that the percentage of cancer stem cells identified in a tumor can be highly variable—a function of the technique used to transplant the cells—and it is conceivable that the absence of appropriate microenvironmental signals from the host limits tumor initiation to only a few cells in this artificial condition. While some studies in syngeneic mouse models in which the host microenvironment is intact have demonstrated that the capacity to re-initiate the tumor is indeed limited to a small population of prospectively identifiable cells, it remains to be seen whether this is true across all syngeneic mammary tumor models—and even harder to prove, across any or all in situ human tumors. Concordance between findings in syngeneic mouse models and human tumor xenografts is reassuring, however. In a novel study with parallel findings in both systems, Atkinson et al have recently demonstrated the proof in principle that sub-lethal radiation alone can shrink the tumors but enrich for the resistant tumor-initiating cells in both p53 null mammary tumors and triple negative human xenografts. In contrast, the combination of hyperthermia and radiation simultaneously decreases both the tumor bulk and the tumor-initiating capacity. Rigorous therapy-based studies in multiple models, such as this report by Atkinson et al, suggest that the potential caveats regarding anti–cancer stem cell therapies, including the possibility of dedifferentiation by differentiated cells to replace targeted cancer stem cells, may not be insurmountable obstacles.
Ultimately, proving the value of cancer stem cell studies will require clinical data demonstrating that targeting cancer stem cells improves breast cancer survival. If the biology of normal stem cells teaches us something about the biology of cancer that leads to more cures, it will not matter whether the cells are stem cells, progenitors, tumor-initiators, or self-renewing cells. For now, though, it remains unclear whether breast cancer stem cell targets represent the heart of the beast or just something at which to aim.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.