Cancer Stem Cells

Abstract

Solid tumors are comprised of a surprisingly heterogeneous collection of cells. As discussed in an introductory talk by Dr. Rudin, recent studies focused on a wide diversity of malignancies have begun to define phenotypically distinct subsets of cancer cells that differ in terms of both clonogenic potential in vitro and tumorigenic potential in vivo. These studies have been interpreted by many as supporting the cancer stem cell hypothesis.1 In brief, this hypothesis holds that a small subpopulation of cancer cells within a tumor retain the unique proliferative and differentiative capacity to regenerate tumors. In contrast, the majority of cells within tumors has limited replicative potential and may represent terminally differentiated progeny of the cancer stem cells. An increasingly broad and consistent body of evidence, from both hematologic malignancies and solid tumors, supports that separable phenotypically distinct populations of cancer cells have radically different regenerative capacities. Even very small numbers of purified populations of high-tumorigenic capacity can be successfully transplanted, resulting in tumors consistently recapitulating the full heterogeneity of cell morphologies present in the tumor of origin.1 Several recent articles have sought to define characteristics of putative stem cells for human lung cancer. Ho et al.2 demonstrated that bulk tumor cell sorting from non-small cell lung cancer (NSCLC) cells lines by flow cytometry can be used to isolate a subset of cells markedly enriched for tumorigenic potential in vivo. Eramo et al.3 demonstrated, across all major lung cancer histologies, that a subset of tumor cells expressing elevated CD133 (a known marker of tumor progenitor cells in glioblastoma) is highly tumorigenic and recapitulates the full diversity of CD133-high and low cells in recipient animals. Most recently, Jiang et al.4 used a series of primary xenograft small cell lung cancer to demonstrate that the transcription factor ASCL1, implicated in multiple embryonic developmental pathways, is markedly upregulated in the CD133+ progenitor cell compartment. ASCL1 was found to be a transcriptional regulator of CD133 and suppression of ASCL1 by shRNA markedly inhibited clonogenic potential. Taken together, these recent articles strongly support the existence of a subpopulation within human lung cancers characterized by markedly elevated tumorigenic capacity.