Latency, microenvironment, and the priming of a precancerous senescent cell for malignant transformation

The emergence of cancer is a multistep process, with passage through a so-called precancerous stage as part of the development. Biopsies of suspicious lesions often reveal cells that are altered or abnormal, and those anomalous cells, while often still benign, indicate local conditions conducive to carcinogenesis. Most of the altered cells never develop into cancers, and it is unknown what may trigger malignancy. This report reexamines existing data to provide insights into the conditions necessary to prime a relatively benign and latent cell with malignant potential to respond to a stimulus and transform into cancer. I propose that normal, well-established reactions to cellular insults over time induce conditions within the affected cell which predispose it to malignant transformation. Then, cumulative, age-related changes in the stromal milieu, from a burgeoning population of senescent cells, inadvertently facilitates the progression of mutant cells, contributing to the increase in late life cancers, via incremental seclusion from normal somatic tissues. Within an increasingly exclusive compartment, cells begin a cycle of crosstalk upon each other, incrementally modifying the isolated population of cells with multiple dynamic morphogen gradients that converge, amplify, and erase epigenetic memory within the innermost cells, reprogramming them to a stem cell-like state, and priming them to transform into a novel tissue.