Cancer, aging and the optimal tissue design

Abstract

Division patterns or mammalian tissues, like every other feature of life, have been subject to evolutionary pressures throughout the natural history. A particular and very important design principle that we discuss in this paper is the protective role of tissue architecture against cancer. We present a stochastic dynamical model of cell renewal of epithelial tissue (colonic crypts) which explicitly includes asymmetric indefinite divisions of stem cells and symmetric, finite divisions of daughter cells. We find that the hierarchical structure of crypts plays a protective role against accumulation of double-mutants. We argue that daughter cells, and not only stem cells, can play a role in carcinogenesis. Our model also predicts the optimum number of stem cells per crypt. In most cases, higher numbers of stem cells per crypt correspond to lowering the chance of colon cancer initiation (except if mutation rates associated with daughter cells are a lot lower than those associated with stem cells). Finally, we argue that the evolutionarily optimum which corresponds to a large number of stem cells per crypt, pushes the onset of cancer to an olderx age, but it actually acts against older individuals by increasing their chance of developing cancer.

Introduction

The normal functioning of colon relies on the fine-tuned balance of the epithelial cell production, differentiation and death. The regulation of the processes of cell proliferation and shedding occurs at the level of crypts – the folds of colonic epithelium which are continuously renewed by stem cell division. The appearance of dysplastic crypts in the beginning of colorectal cancers is a manifestation of the broken balance between cell division and apoptosis. At the molecular level, it has been shown that the earliest event of sporadic colorectal cancers is the inactivation of the APC gene [1], [2], or other genes involved in the Wnt pathway [3], [4]. The APC gene inhibits members of the Wnt signaling pathway, which promote the expression of $\beta$-catenin. In its turn, $\beta$-catenin acts as an enhancer of cell division [5].

$10^{10}$cells are replaced daily in a human colon [6]. This makes colon (like other fast-turnover, epithelial tissues) a vulnerable spot for generating malignant mutants. Quoting ref. [7], “the evolutionary imperative of vertebrates has been to find a way to allow cell proliferation when needed, while at the same time efficiently suppressing the genesis of mutated cells leading to deregulated growth”. The cellular architecture of a colon is a fine example of an evolutionary design where the probability of malignant transformation is in some sense minimized. Tissue design of the colon is shaped by the evolutionary pressure to reduce the likelihood of cancer in young individuals, to improve their chance of survival and reproduction. How this affects the architecture of a colon, and what consequences this process has on cancer incidence in the older age is the topic of the present paper.

In what follows, we will review some facts about the structure of a colon, with the main emphasis on the balance between stem cells and daughter cells. Then we will discuss the roles of stem cells and transit/differentiated cells in generation of cancer. Next, we will define what it means to have an “optimal solution” for crypt design from the point of view of evolutionary dynamics. We will talk about a mathematical approach which can infer the optimal design based on the requirement that cancer onset should be pushed as far in age as possible. It turns out that what’s good for the young may be bad for the old. This will then be discussed in relation to cancer as a disease of the elderly.