Figure 1.

Therapy resistance is promoted by genotoxic treatment-induced damage responses in the tumor microenvironment. The local environment in which most neoplasms originate is a complex ecosystem comprised of cancer cells, benign resident cells and transient cells---such as inflammatory cell types, and includes additional structural and soluble components. Genotoxic cancer therapeutics induce DNA damage in tumor cells which can lead to cell death or senescence, but also exerts genotoxic stress in benign cells such as tumor-associated fibroblasts comprising the tissue stroma. DNA damage and other stressors initiate damage response programs, for example the DDR, with several effector arms including the generation and secretion of a diverse spectrum of cytokines, growth factors, and proteases here denoted the DNA Damage Secretory Program (DDSP). Individual components of the DDSP are well-known to promote inflammation, angiogenesis, epithelial-to-mesenchymal transition, tumor cell proliferation, and augment resistance to cancer therapeutics. Targeting individual DDSP components or key upstream master regulators (e.g. NFkB, p38MAPK, PARP) may enhance the effectiveness of commonly used anti-neoplastic agents by suppressing microenvironment-derived resistance mechanisms.

CC, Cancer Cell; RCC, Resistant Cancer Cell; SC, Stromal Cell; EC, Epithelial Cell; IC, Inflammatory Cell; BV, Blood Vessel; DDR, DNA Damage Response; DDSP, DNA Damage Secretory Program.