The therapeutic promise of the cancer stem cell concept

Abstract

Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for those malignancies that are currently refractory to conventional anticancer agents directed predominantly at tumor bulk populations.

Figure 1. CSCs, carcinogenesis, tumorigenesis, and tumor resistance.

(A) Tumors can arise from somatic cells through genetic mutations of cancer-critical genes. In addition, dysregulation of microenvironmental factors can contribute to the carcinogenic process. Such events might predominantly affect long-lived somatic stem cells, which can represent the cancer cell of origin, for example in mouse models of colorectal cancer (48). However, the CSC definition does not imply a specific relationship between CSCs and physiological stem cells. Findings in other disease models support progenitors or terminally differentiated somatic cell types as the source of malignant transformation. (B) CSCs are posited to be exclusively capable of driving tumorigenesis through 3 defining features: (i) their ability for long-term self-renewal, (ii) their capacity to differentiate into tumor bulk populations devoid of CSC characteristics, and (iii) their unlimited potential for proliferation and tumorigenic growth. Furthermore, CSCs in certain malignancies possess the capacity to drive tumor angiogenic responses and/or to engage in vasculogenic mimicry, potential means of promoting tumor growth. In addition, immunoevasive features of CSCs might contribute to tumorigenesis and ultimately to tumor progression. (C) CSCs can exhibit increased resistance to chemotherapeutic agents and/or ionizing radiation. CSCs might also possess a preferential capacity to withstand immune-mediated rejection. If CSCs indeed represent the pool of resistant cells in human cancer patients, they likely also drive neoplastic progression, tumor recurrence, and metastasis. Although this hypothesis requires further validation, clinical tumor progression has already been correlated with CSC frequency in human melanoma patients.

Figure 2. The therapeutic promise of CSC-directed targeting strategies.

A number of therapeutic strategies directed at CSCs are beginning to be experimentally validated. These approaches could potentially enhance responsiveness to current anticancer treatment regimens and might reduce the risk of relapse and dissemination. The approaches include ablation using antitumor agents that target prospective markers of CSCs (e.g., monoclonal antibodies and activated immune cells); reversal of chemo- or radioresistance mechanisms operative in CSC; CSC pathway interference; differentiation therapy; disruption of protumorigenic CSC-microenvironment interactions; antiangiogenic or antivasculogenic therapy; and disruption of immunoevasion pathways.