Chemotherapeutic resistance: surviving stressful situations

Abstract

Chemotherapeutic regimens involve the systemic administration of genotoxic compounds that induce cancer cell death via well-established DNA damage response signaling networks. Less understood is how the treatment of other cell types within the tumor microenvironment affects the therapeutic response. Here we discuss recent work that shows that tumor-adjacent cells can respond to genotoxic stress by activating a paracrine secretory program. Although this secretory response serves to protect progenitor cells and promote tissue regeneration in conditions of cellular stress, it can also be coopted by tumor cells to survive frontline chemotherapy. Thus, local prosurvival signaling may present a fundamental barrier to tumor clearance by genotoxic agents, suggesting that effective treatments need to target both cancer cells and the tumor microenvironment.

Figure 1

A diagram showing microenvironment-specific responses to front-line chemotherapy. (Left) Systemic chemotherapy can effectively clear the majority of lymphoid tumor cells. (Right) However, genotoxic damage can also engage organ and cell-type specific stress responses. Paracrine pro-survival signaling in select tumor microenvironments can counter the efficacy of anti-cancer agents, leading to the persistence of minimal residual disease.