7 research outputs found
Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis
SummaryHerein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible âmetastatic conditioningâ in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments
A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal
Summary: VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies (âsenotherapeuticsâ)âparticularly those that block SASP regulationâmay improve outcomes in patients after VEGFR TKI failure. : Mastri et al. show that resistance to antiangiogenic therapy can induce senescence-mimicking secretory phenotypes that contribute to tumor promotion when treatment is stopped. Therapeutic targeting of senescence secretory regulators such as IL-6 and mTOR could improve outcomes after treatment failure. Keywords: antiangiogenic therapy, secretome, senescence, SASP, IL-6, mTOR, VEGF RTKI, resistance, metastasis, reboun
Down-regulation of DNA mismatch repair protein in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents
Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesionâmediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors
Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents
Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells
Background: Interferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1)-a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells-is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFNrelated secretory changes in preclinical models of acquired resistance
Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression
Summary: Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity