Colon cancer stem cells: implications for prevention and therapy

Abstract

The recent identification of colon cancer tumor-initiating cells adds further support to the cancer stem cell hypothesis. Ongoing basic and translational research efforts are aimed at gaining an increased understanding of the biology of these cells, as well as methods of targeting them. In addition, the relationship between colon carcinogenesis and inflammatory conditions, such as longstanding colitis and inherited syndromes, might be linked to the effect of the processes on stem cells in the colon. This review summarizes current literature on colon cancer stem cells and proposes strategies aimed at targeting these cells for colon cancer prevention and therapy.

Figure 1

Stem cell models in the colon. (a) Normal. During the normal state, each crypt has rare stem cells located near the base of the crypt. Constituents of the surrounding microenvironment include the endothelium, stromal fibroblasts and immune cells, including monocytes and lymphocytes. (b) The colon stem cell in familial adenomatous polyposis (FAP). In this genetic or cell autonomous state, the WNT pathway is activated owing to a functional abnormality in the adenomatous polyposis coli (APC) protein. The defect in this protein permits β-catenin to translocate to the nucleus to activate downstream transcription factors and growth-related targets. This results in the generation of a large number of ‘pre-neoplastic’ colon polyps. (c) The colon stem cell in inflammatory bowel disease. In this state, stem cell self-renewal is driven by extrinsic, or cell non-autonomous, production of cytokines and growth factors in response to injury and subsequent regeneration and repair. The microenvironment, including the monocytes, lymphocytes, fibroblasts and endothelium, all influence the stem cells, which normally participate in tissue repair. However, expanded stem cells also provide targets for further carcinogenic events. Abbreviations: HGF, hepatocyte growth factor; γIFN, gamma interferon; Tcf/Lef, T-cell factor/lymphocyte-enhancing factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Figure 2

The adenoma-to-carcinoma sequence: influence on the colon stem cell. In the normal state, there are rare stem cells at the base of the crypt. When either extrinsic or intrinsic influences occur, increased numbers of stem cells become malignant and invasion of the abnormal cells progresses. As disease progresses further, metastasis might be seen in the liver. Abbreviation: BM, basement membrane.

Figure 3

Therapeutic strategies targeting the colon cancer stem cell. Depicted in this figure are multiple approaches to destruction of the colon cancer stem cell. (a) Prevent homing of the cancer stem cells. There are some proponents of the possibility that cells external to the local environment migrate to sites of malignancy, or indeed are the genesis of malignancy. This strategy would prevent cells external to this microenvironment from establishing residence in the local milieu. (b) Target the cancer stem cell signaling pathway. Pathways unique to the colon cancer stem cell would be targets for novel agents. Combination therapy would then facilitate obliteration of these rare cells. (c) Accelerate differentiation. In this modality, medical therapies for enhancing differentiation would promote the destruction of colon cancer stem cells by conventional chemotherapy. (d) Target the cancer stem cell niche. New strategies invoke approaches aimed at the environment that supports the cancer stem cell, thus preventing further proliferation and spread of the malignancy.