Editors' ChoiceMEDICINE

Limiting damage but promoting resistance

Sci. Signal.  04 Oct 2016:
Vol. 9, Issue 448, pp. ec232
DOI: 10.1126/scisignal.aal1293

Chemotherapy kills tumor cells by damaging cellular integrity, most commonly to that of the DNA. To limit cell death from this damage and the cellular stress that it causes, tumor cells may enter a senescent state, sometimes long-term, which is associated with a change in the production and secretion of various proinflammatory cytokines and growth factors that collectively is termed the senescence-associated secretory phenotype (SASP). Nonmalignant stromal cells in the tumor microenvironment are also damaged by chemotherapy. Bent et al. examined the response of vascular endothelial cells to chemotherapy and found that these cells exhibited an atypical, restrained response to chemotherapy—called acute stress-associated phenotype (ASAP)—that may limit damage to the vasculature but promote chemoresistance in lymphoma cells (see also Georgilis and Gil). SASP-associated cytokine secretion is typically mediated by nuclear factor–κB (NF-κB) activity, and increased secretion of the proinflammatory cytokine interleukin-6 (IL-6) correlates with chemoresistance in the Eµ-myc;p19Arf–/– mouse model of B cell lymphoma and with poor prognosis in B cell lymphoma patients. When assessed 24 hours after exposure, the DNA damaging agent doxorubicin induced an increase in the abundance of senescent markers in human umbilical vein endothelial cells (HUVECs) in culture. However, in contrast to the persistent NF-κB–mediated SASP observed in cultured hepatic carcinoma cells (HCCs), doxorubicin induced a relatively less enduring (˂5 day) and NF-κB–independent increase in secretion of IL-6 from HUVECs. Additionally, doxorubicin induced the secretion of fewer SASP-associated cytokines and growth factors in HUVECs than in HCCs. In addition to its direct role in damaging DNA, doxorubicin induces reactive oxygen species (ROS), which triggers inflammatory cytokine production by activating the mitogen-activated protein kinase (MAPK) p38. Whereas the DNA damage response kinase ATM was indispensable, various assays indicated that ROS and p38 mediated the less prolonged secretion of IL-6 in response to doxorubicin in HUVECs. Protein array–based analysis revealed that the activity of the pathway mediated by the kinases PI3K, AKT, and mTOR was repressed in doxorubicin-exposed HUVECs. Activation of the pathway in HUVECs induced sustained secretion of IL-6 and other SASP-associated factors, as well as morphological senescent phenotypes. Increased abundance of IL-6 lasting less than 4 days (a relatively transient response) occurred in the thymus of doxorubicin-treated Eµ-myc;p19Arf–/– mice, and endothelial-specific knockout of Il-6 reduced tumor burden in mice implanted with Eµ-myc;p19Arf–/– lymphoma cells. It is unclear precisely how the PI3K-AKT-mTOR pathway is suppressed in endothelial cells after chemotherapy to limit senescence, but the findings suggest that this is a protective mechanism in endothelial cells and that their relatively acute response nonetheless may contribute to tumor progression and chemoresistance.

E. H. Bent, L. A. Gilbert, M. T. Hemann, A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 30, 1811–1821 (2016). [PubMed]

A. Georgilis, J. Gil, Controlling secretion to limit chemoresistance. Genes Dev. 30, 1791–1792 (2016). [PubMed]