Intestinal stem cells and the colorectal cancer microenvironment

Abstract

Colorectal cancer (CRC) remains a highly fatal condition in part due to its resilience to treatment and its propensity to spread beyond the site of primary occurrence. One possible avenue for cancer to escape eradication is via stem-like cancer cells that, through phenotypic heterogeneity, are more resilient than other tumor constituents and are key contributors to cancer growth and metastasis. These proliferative tumor cells are theorized to possess many properties akin to normal intestinal stem cells. Not only do these CRC "stem" cells demonstrate similar restorative ability, they also share many cell pathways and surface markers in common, as well as respond to the same key niche stimuli. With the improvement of techniques for epithelial stem cell identification, our understanding of CRC behavior is also evolving. Emerging evidence about cellular plasticity and epithelial mesenchymal transition are shedding light onto metastatic CRC processes and are also challenging fundamental concepts about unidirectional epithelial proliferation. This review aims to reappraise evidence supporting the existence and behavior of CRC stem cells, their relationship to normal stem cells, and their possible dependence on the stem cell niche.

Keywords: Cell dedifferentiation; Colon cancer stem cells; DCLK1 protein; Stem cell niche.

Figure 1

Origin and development of normal intestinal stem cells. Lgr5⁺ CBCs and +4 LRCs coexist in the crypt. Each stem cell is fully multipotent. Lgr5⁺ cells likely maintain intestinal homeostasis under normal conditions. Following intestinal injury, the reserve population comprised of +4 LRCs and Dll1⁺ secretory progenitors restore both the epithelium and Lgr5⁺ CBCs. Tuft cells are Bmi1⁺ cells that may be synonymous with or descendants of +4 LRCs. CRC: Colorectal cancer; CBCs: Crypt base columnar cells; LRCs: Label-retaining intestinal stem cells.

Figure 2

Niche regulation of the normal intestinal epithelium and colorectal cancer. A: Intestinal subepithelial myofibroblasts (ISEMFs) surround the crypt. Along with paneth cells (P), they supply the stem cell niche with trophic signals. Developing intestinal cells migrate upwards towards the villus apex, during which time they are subject to niches among the various strata in the crypt. B: Redundant mediators expressed by ISEMFs and Paneth cells contribute to the preservation of the stem cell compartment and normal intestinal proliferation. C: The local niche immediately around CRC likely fosters tumor growth by activating stem cell pathways. CRC cells lacking proliferative ability may re-awaken upon re-entry into the niche. CRC: Colorectal cancer; BMP: Basic metabolic panel.

Figure 3

Epithelial-mesenchymal transition and mesenchymal-epithelial transition in colorectal cancer. In a primary tumor, CRC stem cells exist in a stationary phase that promotes growth. EMT transition to a migratory mesenchymal phase deactivates proliferative genes and cell adhesion molecules, generally allowing for metastatic dissemination to occur. Once at distant targets, mesenchymal cells transition back to the stationary phase via MET thereby resuming tumor expansion. EMT: Epithelial-mesenchymal transition; MET: Mesenchymal-epithelial transition; CRC: Colorectal cancer.