The Lifelong Generative Capacity of Stem Cells Determines Cancer Risk

Cancers occur at different frequencies in an organ- and age-specific manner, partly due to organ-specific vulnerabilities to extrinsic factors such as carcinogens. Recently, the cumulative lifetime number of stem cell (SC) divisions in a tissue has been proposed as an intrinsic factor that may contribute to disparities in cancer risk, but varied mathematical approaches have resulted in different estimations regarding the impact of SC replication on cancer risk. To directly define cellular properties that determine cancer risk, Zhu and colleagues performed organism-wide Cre-mediated recombination of conditional lineage tracing, oncogenes, and tumor suppressor genes (TSG) in defined cell populations to assess the lifetime risk of organ-specific cancers. Cells positive for prominin 1 (Prom1), which is a marker for SC-containing cell populations in multiple mouse organs and for normal and tumor human SCs, exhibited a significant range of generative capacities among different organs. In vivo recombination of conditional alleles of oncogenes or TSGs, singly or in combination, in PROM1⁺ SCs showed that PROM1⁺ SCs exhibited both organ- and developmental stage–specific susceptibility to initiating mutations. Further, it was shown that the formation of PROM1⁺ cell–derived tumors was dependent upon both the type of initiating mutation and the generative capacity of PROM1⁺ cells. Consistent with these findings, injury of adult hepatic PROM1⁺ cells, which were postulated to be the quiescent progeny of highly generative neonatal hepatic PROM1⁺ SCs, resulted in a damage-induced increase in generative capacity and a consequent increase in susceptibility to transformation, suggesting that extrinsic factors can induce the expansion of the SC population and thus increase organ-specific cancer risk. Together, these findings experimentally define a model of organ-specific cancer risk in which extrinsic factors induce SC proliferative repair by mutagenesis and/or tissue damage and subsequently the intrinsic generative capacity of organ SCs determines the risk of organ-specific tumorigenesis.

Zhu L, Finkelstein D, Gao C, Shi L, Wang Y, Lopez-Terrada D, et al. Multi-organ mapping of cancer risk. Cell 2016;166:1132–46.