Controlling secretion to limit chemoresistance

Abstract

The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue, Bent et al. (2016) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation

Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors

“…Exactly how broadly TME inhibitors, including widely-used agents targeting angiogenesis and immune-checkpoints, can influence secretory programs remain unclear(2,5). TIS programs may derive from tumor cell populations, and thus may provide information about cancer stage and response, but may also derive from non-tumor ‘host’ cell populations(4,10). For example, a diverse array of secretory proteins can be induced in patients’ blood by inhibitors of the VEGF pathway that include receptor tyrosine kinase inhibitors (RTKIs), or antibodies that disrupt VEGF:VEGFR signaling(11,12).…”

Prodrug Nanomedicine Inhibits Chemotherapy-Induced Proliferative Burst by Altering the Deleterious Intercellular Communication

“…23 A genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics indicated that treatment-induced damage to the tumor microenvironment, especially the fibroblasts, promotes an epithelial to mesenchymal transition (EMT) in neoplastic prostate epithelium and promotes the survival of cancer cells after cytotoxic therapy through wingless-type MMTV integration site family (mostly WNT16B). 16 Even though the activation of specific senescence-associated secretory phenotype (SASP) or acute stress-associated phenotype (ASAP), 25 which promotes drug resistance and metastasis, could be diminished by blocking corresponding signaling pathways 23 or by exempting senescence-sensitive cells with some selective killing strategies, 15 the complexity of the TME and the limited knowledge about those unknown detrimental pathways could greatly compromise the efforts. Therefore, in addition to screening particular drugs to inhibit a specific pathway, 26−29 an important issue to tackle the therapyinduced proliferation burst during treatment might be the selective elimination of those uncontrollably and malignantly proliferated cancer cells without further promoting detrimental intercellular communications.…”

“…Even though the activation of specific senescence-associated secretory phenotype (SASP) or acute stress-associated phenotype (ASAP), which promotes drug resistance and metastasis, could be diminished by blocking corresponding signaling pathways or by exempting senescence-sensitive cells with some selective killing strategies, the complexity of the TME and the limited knowledge about those unknown detrimental pathways could greatly compromise the efforts. Therefore, in addition to screening particular drugs to inhibit a specific pathway, − an important issue to tackle the therapy-induced proliferation burst during treatment might be the selective elimination of those uncontrollably and malignantly proliferated cancer cells without further promoting detrimental intercellular communications.…”

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

“…For this reason, early-stage reversible/uncommitted senescence phenotypes have been variously called ''premature,'' ''pseudosenescent,'' ''short-lived,'' ''senescence-like,'' or ''accelerated'' (Kim et al, 2014;Demaria et al, 2014;Gewirtz et al, 2008), and may be distinct from senescence induced by replication or oncogenes (reviewed in Ewald et al, 2010;Gewirtz et al, 2008;Saleh et al, 2018;Chakradeo et al, 2016). For instance, doxorubicin can induce a limited senescence in endothelial cells (Bent et al, 2016), and there are several additional examples as well (Georgilis and Gil, 2016;Bent et al, 2016;Obenauf et al, 2015;Chakradeo et al, 2016). Importantly, our results also compliment prior studies showing Su-induction of senescence or senescence-related regulators, including NF-kB (Sanchez et al, 2013) and IL-6 (Zhu et al, 2015), SA-b-gal (Andrae et al, 2012), p53 (Zhu et al, 2013), and mTOR (Elgendy et al, 2017;Jimé nez-Valerio et al, 2016).…”