Cancer comes of age embryonically

incidence of cancer increases exponentially with age. Aging may lead to pathologies due to the physiologic decline or aberrancy in the functions of adult stem cells, whose intrinsic capacity for self-renewal helps maintain tissue homeostasis. The majority of cancers arise from replication-induced somatic mutations in adult stem cells [1], which predisposes to hijacking their self-renewal pathways to drive tumor development. Yet the modulation of stem cell signaling by oncogenic driver mutations in cancer initiation is not well characterized. The hierarchically structured colon epithelium presents an ideal in vivo cancer model to assess the step-wise malignant transformation of crypt base colon stem cells into colon adenoma and carcinoma cells. Hitherto, the initiation of colon cancer has been attributed mainly to the aberrant activation of WNT signaling as a result of APC or CTNNB1 mutations, which are found in >90% of early colon adenomas [2]. Indeed, it has been suggested that the development of oncogenic KRAS mutation (KRAS mut) in late colon adenomas drive their malignant transformation to cancer by further promoting WNT activation through β-catenin nuclear localization [3]. However, aberrant WNT signaling per se, even when targeted to murine colon stem cells to constitutively activate their intestinal stem cell program, was capable of initiating colon adenomas but not invasive colon cancers [4]. Nearly all colon cancers originate from colon adenomas, yet ≤ 5% of colon adenomas ultimately transform into colon cancers [5]. Thus the biologic programs driving colon cancer initiation, which is best defined as the direct malignant transformation of colon adenomas into stage I colon cancers, are distinct from the premalignant activated WNT program that is responsible for colon adenoma initiation. We have found that embryonic stem cell-like program activation is a major mechanistic driver of colon cancer initiation, and the presence of KRAS mut further increases this tumorigenic and dedifferentiation program [6]. The ability of KRAS mut to dedifferentiate APC mutated colon adenoma cells depends on their moderate plasticity, since KRAS mut by itself in the cellular context of differentiated epithelial cells cannot induce the embryonic stem cell-like program [6, 7]. We have proposed an in vivo plasticity model in which the Editorial achievement of high plasticity, as exemplify by KRAS mut mediated induction of the embryonic stem cell-like program in colon adenomas, optimizes colon cancer initiation. Currently, there are two conflicting theories for the colon cancer cells of origin. The top-down theory requires that differentiated crypt top colon …