Optimizing radiotherapy and chemotherapy for the treatment of malignant neoplasms has relied on the iterative development and testing of models involving tumor growth dynamics, mutation rates and cell-kill kinetics. However, the most theoretically effective tumoricidal strategies must usually be tempered because of detrimental effects to the host. This reality has led to the development of regimens in which therapies are administered at intervals or cycles to avoid irreparable damage to vital host functions. However, the recovery and repopulation of tumor cells between treatment cycles is a major cause of treatment failure15,16
. Interestingly, rates of tumor cell repopulation have been shown to accelerate in the intervals between successive courses of treatment, and solid tumors commonly show initial responses followed by rapid regrowth and subsequent resistance to further chemotherapy. Our results indicate that damage responses in benign cells comprising the tumor microenvironment may directly contribute to enhanced tumor growth kinetics ().
The autocrine- and paracrine-acting influences of genotoxic stress responses can exert complex and potentially conflicting cell non-autonomous effects33,34
. Overall, our findings are in agreement with studies of DNA damage in which the execution of a signaling program culminating in a senescence phenotype is accompanied by elevated concentrations of specific extracellular proteins termed a ‘senescence messaging secretome’ or a ‘senescence-associated secretory phenotype’33,34
. DNA damage responses and senescence programs can clearly operate in a cell autonomous ‘intrinsic’ manner to arrest cell growth and inhibit tumor progression, as has been observed in premalignant nevi35
. Secreted factors such as insulin-like growth factor binding protein 7 (IGFBP7) and the chemokine (C-X-C motif) receptor 2 (CXCR2) ligands IL-6 and IL-8 participate in a positive feedback loop to fortify the senescence growth arrest induced by oncogenic stress and also promote immune responses that clear senescent cells and enhance tumor regression23,32,36,37
. However, in addition to proinflammatory cytokines, the damage response program comprises proteases and mitogenic growth factors, such as MMPs, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) ligands that have clear roles in promoting tumor growth, inhibiting cellular differentiation, enhancing angiogenesis and influencing treatment resistance19,20,38
. This concept is supported by reports of tissue-specific chemoresistant survival niches involving hematopoietic neoplasms, such as lymphomas39
. The situation also has parallels with studies of radiation and chemotherapy paradoxically promoting tumor dissemination40
Collectively, these studies support several conclusions: first, the outcomes of genotoxic exposures to any specific benign or neoplastic cell depend on the integration of innate damage response capabilities and the context that is dictated by the composition of the tumor microenvironment; second, although intrinsic drug resistance is clearly operative in some cancers, acquired resistance can also occur without alterations in intrinsic cellular chemosensitivity41
, and our results provide strong support for previous studies that implicate constituents of the tumor microenvironment as important contributors to this resistance42–44
; and third, specific microenvironment DDSP proteins that promote therapy resistance such as WNT16B are attractive targets for augmenting responses to more general genotoxic therapeutics. However, the complexity of the damage response program also supports strategies that are focused on inhibiting upstream master regulators, such as NF-κB45
, that may be more efficient and effective adjuncts to cytotoxic therapies, provided their side effects are tolerable.