title: 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.
authors.affiliation: Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Gilbert
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual; D019899:Paracrine Communication / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism*; D013934:Thymectomy; D013950:Thymus Gland / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D015850:Interleukin-6; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases