Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis

Abstract

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/beta-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

Figure 1

CSC-sensitizing agents in radiation therapy and chemotherapy. Tumors contain both CSCs (pink) and non-stem cancer cells (yellow). CSCs may preferentially survive monotherapy with ionizing radiation (A) or cytotoxic chemotherapies (C), leading to tumor repopulation and disease recurrence. Targeting CSC-specific therapeutic resistance mechanisms like Chk1/2 activation (B) or IL-4 signalling (D) could sensitize tumors to these treatments.

Figure 2

Anti-angiogenic agents may target both tumor vasculature formation and CSC niche maintenance. (A) CSCs generate pro-angiogenic factors to stimulate angiogenesis while the tumor vasculature aids in maintaining CSC self-renewal and maintenance. (B) Anti-angiogenic agents like anti-VEGF therapies or low molecular weight kinase inhibitors disrupt angiogenesis and may also interrupt vascular-derived CSC maintenance cues.