The role of colorectal cancer stem cells in metastatic disease and therapeutic response

Abstract

Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These "cancer stem cells" (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer.

Figure 1.

Diagram of the human colonic crypt structure. (Left) The stem cell compartment resides at the base of the crypt. Rapidly dividing transit-amplifying (TA) cells arise from this population and differentiate into the functional cells of the colon. (Right) The source of the colon CSC remains controversial. A single transforming mutation in a somatic intestinal stem cell could give rise to a CSC, while two mutations (one transforming and one de-differentiating) would be required to change a TA or differentiated colonic cell into a CSC.

Figure 2.

Colorectal cancer (CRC) has better survival odds than metastatic CRC (mCRC) or young-adult CRC (YA-CRC). The difference in disease response to the current state-of-the-art treatment reflects a gradient of disease with the early staged primary CRC (1°CRC) responding more favorably than late stage CRC, YA-CRC or mCRC. The variability in treatment response is likely dependent upon differences in molecular and cellular characteristics among the disease spectrum. The current challenge is to understand these differences to inform targeted therapy with the ultimate goal of cancer eradication.

Figure 3.

(A) Classical hierarchical model of tumorigenesis where any tumor cell has the potential and capacity to recapitulate the tumor, thus giving rise to tumor heterogeneity. (B) In the cancer stem cell (CSC) model of tumorigenesis, only CSCs have the potential to recapitulate the tumor. All other tumor cells are “differentiated.” Tumor heterogeneity arises as the result of mutations in the CSC and differentiation of its progeny.

Figure 4.

Clinical implications of the CSC model. Systemic chemotherapy and loco-regional radiation therapy affect the more differentiated tumor cells but not the CSC. Following therapy, the treatment-resistant CSC remains and is able to re-populate the tumor and give rise to additional treatment-resistant CSC progeny as well as chemotherapy-sensitive differentiated cells. Clinically, this is seen as disease relapse. Further treatment with standard cytotoxic and biologic therapies will result in increasing numbers of CSCs, which presents clinically as progressive, completely treatment-resistant disease.