Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer-related death. Significant improvements in CRC treatment have been made for the last 20 years, on one hand thanks to a better detection, allowing surgical resection of the incriminated area, and on the other hand, thanks to a better knowledge of CRC's development allowing the improvement of drug strategies. Despite this crucial progress, CRC remains a public health issue. The current model for CRC initiation and progression is based on accumulation of sequential known genetic mutations in the colon epithelial cells' genome leading to a loss of control over proliferation and survival. However, increasing evidence reveals that CRC initiation is more complex. Indeed, chronic inflammatory contexts, such as inflammatory bowel diseases, have been shown to increase the risk for CRC development in mice and humans. In this manuscript, we review whether colon fibroblasts can go from the main regulators of the ISC homeostasis, regulating not only the renewal process but also the epithelial cells' differentiation occurring along the colon crypt, to the main player in the initiation of the colorectal cancer process due to chronic inflammation.

Keywords: colon; colorectal cancer; fibroblasts; inflammation; intestinal stem cells; stroma.

Figure 1

Epithelio-fibroblastic relationship in the physiological and injury context in intestinal tissue. Under the physiological context, normal fibroblasts form a very heterogeneous cell population that could be divide into two families: interstitial fibroblasts (extracellular matrix (ECM) production and regulation) and pericryptic fibroblasts (soluble factors secretion and ECM basement membrane production). Depending on pericryptic fibroblasts’ localization on the intestinal crypt compartment, they secrete (i) proliferating factors for intestinal stem cell (ISC) maintenance (wingless-related integration site (Wnt ligands, R-spondin, EGF, bone morphogenic protein (BMP) antagonists) and constitute an ISC niche or (ii) differentiating factors (BMP family). In the case of acute or chronic tissue injury, not only epithelial cells but also fibroblastic populations undergo a strong remodeling, resulting in ISC loss and/or inability to regenerate epithelium. Depending on the injury severity, resident fibroblasts can be lost or become transiently or definitively activated. Other cell types can differentiate and reach an activated-fibroblast phenotype, thus promoting epithelial regeneration, survival, and immune dialog. Activated fibroblasts can improve epithelial regeneration on a first intention (by increasing some ISC niche factors’ production) and then switch their phenotype to impaired ISC and epithelium renewal.

Figure 2

Fibroblast activation dynamic switch depending on the physiopathological context. Normal fibroblasts have a pivotal role under the physiological context to produce ECM protein, control ISC compartment proliferation/differentiation, and maintain intestinal tissue homeostasis. Fibroblasts are very plastic cells able to respond to their environment by becoming activated in case of injury to support ISC proliferation and renewal. To compensate eventual ISC loss, the intestinal epithelium can call on reserve stem cells, which can be recruited by stromal stimulation, in particular prostaglandin E2 (PGE2), or a dedifferentiation of secretory or fully differentiated progenitors, to join the compartment strain and thereby regenerate the epithelium. After epithelium repair, the activated fibroblasts can either become quiescent again, or regain their physiological function (by dedifferentiation), or die by apoptosis. However, if the injury persists and becomes chronic, the activated fibroblasts are locked into this state (possibly due to changes in the epigenetic status). This is where activated fibroblasts can play an important role in the emergence or initiation of new pathologies such as cancer.

Figure 3

Fibroblast markers and mediators under physiological and pathological contexts. Fibroblasts can be divided into different populations depending on their locations, functions along the crypt axis, and pathophysiological status. More and more studies try to present a panel of markers that can be used to decipher those populations. Although none of them are actually specific of a subpopulation, in combination, they allow the discrimination of the different subpopulations, namely top pericryptic-, bottom pericryptic- and lamina propria-associated fibroblasts. However, discrepancies exist for example concerning alpha smooth muscle actin (αSMA), which can be found, or not, on the different populations. Under the pathological context, the discrimination of the diverse fibroblasts populations is increasingly complex, with no markers being currently known to clearly identify the ones implicated in the various pathological processes. Markers and mediators listed in this figure are used as examples and are not exhaustive.