Oncogene
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EGFL6, a member of the EGF-like superfamily, plays an important role during embryonic development and has been implicated in promotion of tumor angiogenesis without affecting wound healing. There is very little known about the function of EGFL6 in cancer cells. Here, we investigated whether EGFL6 plays a direct role in cancer cells in addition to the promotion of tumor angiogenesis. ⋯ Blockade of EGFL6 using our novel anti-EGFL6 monoclonal antibody significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Silencing EGFL6 mRNA by shRNA transfection of cancer cells also significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Taken together, the results of this study indicate that targeting EGFL6 is a unique strategy for inhibiting both cancer cell metastasis and tumor angiogenesis.
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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 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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Mindin, a secreted, highly conserved extracellular matrix (ECM) protein, exerts a broad spectrum of effects on the innate immune system. However, its function in colorectal cancer (CRC) progression is not well established, and its upstream regulation mechanisms remain unclear. Contrary to previous reports, this study used two different enzyme-linked immunosorbent assay (ELISA) kits to show that the serum level of mindin was significantly decreased in CRC patients and that this decreased level is more significantly associated with the early stages of the disease. ⋯ Overexpression of mindin suppressed xenograft tumor growth by blocking angiogenesis instead of directly suppressing CRC cell proliferation. Mechanically, mindin inhibits the hypoxia-induced HIF-1a and VEGFA protein expression in CRC cells and the phosphorylation of VEGFR-2 in endothelial cells. The results suggest that the serum level of mindin can be used as a novel biomarker for early detection of CRC and that the Egr-1/mindin axis is a potential therapeutic target for the inhibition of angiogenesis in CRC development.
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Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. ⋯ In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.