Therapeutic implications of colon cancer stem cells

Abstract

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

Figure 1

Therapeutic implication of cancer stem cells. The failure of current standard therapies in tumor eradication can be explained by assuming that colorectal cancer stem cells (CRC-SCs) are able to survive treatments leading to an only transitory clinical remission. Therapeutic strategies that specifically target the CRC-SC pool, by eliminating the self-renewing component of the tumor mass, could be more effective in eradicating the tumor and reducing the risk of relapse and metastasis.

Figure 2

Colorectal cancer stem cells as a tool for drug discovery. In vitro, colorectal cancer stem cells (CRC-SCs), isolated from the tumor specimen, are propagated as “tumor spheres”. Membrane marker analysis together with transcriptional, microRNA and proteomic profiling lead to the identification of molecular targets that are expressed by this cell population. These findings can be used to evaluate the cytotoxic ability of new compounds. In vivo, CRC-SCs can be orthotopically and heterotopically injected into immunocompromised mice generating tumors that mimic the cytoarchitecture of the parental tumors. The use of such mouse models of CRC allows for drug testing analyses in order to eradicate the primary tumor and avoid the formation of incurable metastases.