AI Article Synopsis

  • Anti-VEGF therapy shows promise for treating metastatic cancers, but many tumors eventually develop resistance to this treatment.
  • Genomic analysis of resistant ovarian tumors revealed that the MSMP gene is significantly upregulated, which is linked to hypoxic conditions and promotes the formation of new blood vessels.
  • Inhibiting MSMP in combination with anti-VEGF therapy could be a potential strategy to counteract resistance and improve treatment outcomes for ovarian cancer patients.

Article Abstract

Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors. MSMP secretion from cancer cells was induced by hypoxia, triggering MAPK signaling in endothelial cells to promote tube formation in vitro. Recruitment of the transcriptional repressor CCCTC-binding factor (CTCF) to the MSMP enhancer region was decreased by histone acetylation under hypoxic conditions in cancer cells. MSMP siRNA, delivered in vivo using the DOPC nanoliposomes, restored tumor sensitivity to anti-VEGF therapy. In ovarian cancer patients treated with bevacizumab, serum MSMP concentration increased significantly only in non-responders. These findings imply that MSMP inhibition combined with the use of antiangiogenesis drugs may be a new strategy to overcome resistance to antiangiogenesis therapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040890PMC
http://dx.doi.org/10.1038/onc.2017.348DOI Listing

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