Are all cancer stem cells created equal?

Abstract

Numerous solid malignancies have been reported to contain cancer stem cells (CSCs). Distinct functional characteristics have been attributed to CSCs, and thus it is widely believed that these unique cells may have genetic and phenotypic homogeneity. Recent exciting but limited evidence, however, contradicts this tenet and supports the intriguing concept of genetic and phenotypic diversity in the CSC population. We propose that CSC heterogeneity at the inter- and intrapatient levels may be due to the cell of origin, to environmental cues, and/or to human papillomavirus infection. Additional insight into CSC heterogeneity is needed to identify actionable targets for optimal eradication of the diverse CSC subpopulations within a tumor.

Figure 1.

Putative cells of origin for CSCs. Normal stem cells, normal progenitor cells, normal differentiated cells, normal or transformed differentiated cells, and non-CSC tumor cells are proposed as potential cells of origin for CSCs. Abbreviation: CSC, cancer stem cell.

Figure 2.

CSC diversity and intratumor heterogeneity in HPV-negative and HPV16-positive OPSCC. (A): HPV-negative OPSCC. The cell of origin for HPV-negative OPSCC CSCs can include normal stem cells, normal progenitor cells, and differentiated cells leading to interpatient CSC and tumor heterogeneity. A continual cycle of reprogramming of HPV-negative non-CSC tumor cells to HPV-negative CSCs is postulated because of the accumulation of genetic alterations from smoking and/or alcohol exposure. These newly evolved CSCs will have additional genetic alterations beyond the original parental CSC, resulting in an increase in intrapatient CSC diversity and tumor heterogeneity in HPV-negative OPSCC. (B): HPV16-positive OPSCC. The cell of origin for HPV16-positive OPSCC CSCs is limited to the basal stem cells in the reticulated epithelium of the tonsillar crypt. An HPV16-positive OPSCC CSC is thought to undergo symmetric and asymmetric cell division to give rise to a genetically nondiverse population of CSCs and differentiated non-CSC tumor cells, resulting in a homogenous tumor at the genetic level. Abbreviations: CSC, cancer stem cell; HPV, human papillomavirus; OPSCC, oropharyngeal squamous cell carcinoma.