Multi-organ Mapping of Cancer Risk

Abstract

SUMMARY Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene and tumour suppressor alleles to define populations of stem and non-stem cells in mouse organs, and test their life-long susceptibility to tumourigenesis. We show that tumour incidence is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a ‘perfect storm’ that ultimately determines organ cancer risk.

Clonal haematopoiesis is not prevalent in survivors of childhood cancer

“…In light of the above, our findings have two plausible explanations: (i) that somatic driver mutations are very uncommon in young individuals even after exposure to chemotherapy or (ii) that accrual of such mutations is insufficient to trigger clonal expansion in this age group. The latter is supported by findings that oncogenic mutations begin accumulating early in life (Welch et al , 2012) and that cancer‐associated mutations are less able to drive clonal expansion in young compared to old stem cells (Zhu et al , 2016). The fact that bona‐fide driver mutations do not always lead to haematopoietic clonal expansion, even after several years, was highlighted by Young et al (2016), using ultra‐sensitive sequencing.…”

Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

“…CSCs are thought to critically account for tumor heterogeneity, metastasis, and resistance to anticancer therapies3. A series of recent studies obtained direct experimental evidence that genetic mutation of tissue stem cells is an important determinant of cancer risk45, rendering strong support for the CSC model.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…Currently, at least three stem cell populations are known to exist in both mouse27 and human adult liver28: 1) pericentral Axin2 + hepatocytes that can regenerate liver in normal homeostasis29; 2) periportal cells positive for Lgr530; 3) Prom1 + liver stem cells that are located within or adjacent to the Krt19 + bile duct epithelium 31. Human periportal cells also label for octamer 3/4 (Oct3/4), β2 spectrin (β2SP), and TBRII in both human and mouse liver regeneration 27, 28, 32.…”