Counterpoint: Cancer Stem Cells: Nonbelievers' Viewpoint

Abstract

Several studies have identified a subset of cancer cells, designated as tumor-initiating cells or cancer stem cells (CSCs),3 with the ability for self-renewal and differentiation into distinct cell lineages. In recent years, the hypothesis has emerged, and gained great momentum, that tumors are hierarchically arranged, with CSCs being the principal drivers of tumor growth for proliferation, resistance to chemotherapy, and metastasis (1–3). A combination of flow cytometry and xenotransplantation techniques led to the identification of leukemia-initiating cells (CD34+CD38−) and breast cancer–initiating cells (CD44+CD24−/low) and provided the scientific basis for the CSC hypothesis (3–5). Needless to say, if CSCs exist, their attributes need to be studied, and specific therapies directed against these cells will have to be developed. Although there are some excellent studies suggesting the presence of CSCs, several controversial issues remain. The development of drug resistance and disease recurrence and metastasis could simply be consequences of tumor heterogeneity and plasticity. The latter characteristics also could result in cells having distinct characteristics, including sensitivity to therapy. What factors (i.e., clonal evolution, CSCs, or tumor-microenvironment niche) contribute to adverse outcomes remains an important question. The answer to this question is undoubtedly going to be complex and may vary in different tumors. One of the concerns with the CSC hypothesis is that the methods used to identify these cells are limited. The presence of CSCs is usually inferred on the basis of one of the following characteristics: ( a ) flow cytometry results indicating the presence of “specific” cell surface markers; ( b ) clonogenic assay findings such as mammosphere formation; and ( c ) ability of cells to give rise to metastases in xenotransplantation models (6). Several cell surface markers have been associated with CSC activity. These tend to differ across different studies, with minor …