# A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis

## TL;DR

This paper explains how a slowdown in tissue renewal caused by APC mutations leads to colorectal cancer by causing abnormal cell growth and tissue disorganization.

## Contribution

The study proposes a novel mechanism linking APC mutations to tumor formation through altered tissue renewal dynamics.

## Key findings

- Premalignant colonic crypts with APC mutations show a decreased rate of tissue renewal.
- Slower cell polymerization leads to tissue disorganization and epithelial expansion during adenoma formation.
- The mechanism may also apply to tumorigenesis in other cancer types.

## Abstract

Around 90% of colorectal cancer (CRC) tissues have driver APC mutations. Evidence that APC mutation drives tumor initiation and growth comes from familial adenomatous polyposis (FAP) patients who carry an APC germline mutation. If not surgically treated, FAP patients have a 100% risk for developing CRC. Our study of FAP patients evaluated changes in the dynamics of tissue renewal during early colon tumor development. The results show premalignant colonic crypts have a decreased rate of tissue renewal due to APC mutation. This slower rate of cell polymerization causes a rate-limiting step in the crypt renewal process that expands proliferative cell population size. This mechanism explains how a prolonged rate of crypt renewal causes tissue disorganization with local epithelial expansion, infolding, and contortion during adenoma morphogenesis. Since tissue renewal dynamically sustains cell numbers constant in all bodily organs, our findings also have significance in terms of understanding tumorigenesis in other cancer types.

Our Goal is to identify how colorectal cancer (CRC) arises in the single-layered cell epithelium (simple columnar epithelium) that lines the luminal surface of the large intestine. Background: We recently reported that the dynamic organization of cells in colonic epithelium is encoded by five biological rules and conjectured that colon tumorigenesis involves an autocatalytic tissue renewal reaction. Introduction Our objective was to define how altered crypt turnover explains tissue disorganization that leads to adenoma morphogenesis and CRC. Hypothesis: Changes in rate of tissue renewal-based cell polymerization leads to epithelial expansion and tissue disorganization during adenoma histogenesis. Methods: Accordingly, we created a computational model that considers the structure of colonic epithelium to be a polymer of cells and that tissue renewal is autocatalytic. Indeed, self-renewal of stem cells in colonic crypts continuously produces cells that act like monomers to form a polymer of cells (an interconnected, continuous cell sheet) in a polymerization-based process. Our model is a system of nonlinear differential equations that simulates changes in human crypt cell population dynamics. Results: We investigated how changes occur in the proportion of different cell types during adenoma development in FAP patients. The results show premalignant colonic crypts have a decreased rate of tissue renewal due to APC-mutation. Discussion: This slower rate of cell polymerization causes a rate-limiting step in the crypt renewal process that expands the proliferative cell population size. Conclusions: Our findings provide a mechanism that explains how a prolonged rate of crypt renewal leads to tissue disorganization with local epithelial expansion, infolding, and contortion during adenoma morphogenesis.: