Abstract 4987: IL8, VEGF and IGF-1 rescue ovarian cancer cells undergoing ARHI-mediated- autophagic cell death
Authors: Lu Zhen , Orozco Aaron F. , Sutton Margie , Yan Wang , Mao Weiqun , Bast Robert 
Published: August 2015

Each year in the US, more than 22,000 women develop ovarian cancer. Despite progress in surgery and chemotherapy, the disease still proves lethal in 70% of cases. One of the most important factors contributing to poor outcomes is the ability of drug resistant ovarian cancer cells to remain dormant for years after treatment, only to grow progressively and kill their host. Judging from sites of recurrence, most dormant ovarian cancer cells are found on the surface of the peritoneal cavity, often in small, poorly vascularized collagenous scars observed at “second look” operations. Previously, we reported that more than 80% of persistent, dormant drug resistant ovarian cancers express DIRAS3 and are undergoing autophagy. Autophagy can drive cancer cell survival or cell death depending on the context. Our group has found that autophagy and tumor dormancy can be regulated by an imprinted tumor suppressor gene, DIRAS3 (ARHI), which is downregulated in 60% of ovarian cancers. Re-expression of DIRAS3 induces autophagy by inhibiting PI3K and mTOR signaling, displacing Bcl-2 from Beclin to form the autophagy initiating complex, inducing ATG4 and decorating the autophagosome membrane where it co-localizes with LC3II. Re-expression of DIRAS3 in cell culture produces cell death within 72 hours, whereas re-expression of DIRAS3 in xenografts produces cell growth arrest and tumor dormancy. When DIRAS3 levels are reduced after 6 weeks of induction, xenografts grow promptly. Our current experiments were designed to determine whether survival of autophagic cells in vivo requires permissive levels of VEGF, IL-8 and IGF-1 which are often found in the tumor microenvironment. In cell culture, SKOv3-DIRAS3 cells can be rescued from DIRAS3-induced autophagic cell death in culture by co-incubation with VEGF, IGF-1 and IL-8. Treatment with anti-VEGF, anti-IL8 and anti-IGF-1 antibodies, individually and in combination, slowed the outgrowth of dormant autophagic ovarian cancer cells. Treatment of dormant xenografts with the same monoclonal antibodies against VEGF, IL-8 and IGFR with or without CQ not only delayed outgrowth when DOX was withdrawn, but cured a fraction of mice. Re-expression of DIRAS3 reduced expression of IGF-1 receptor, but not VEGF and IL8 receptors. Treatment of ovarian cancer cells with VEGF, IL-8 and IGF-1 reduced DIRAS3's ability to induce autophagy and inhibit both AKT and mTOR activity. These preclinical studies lay the groundwork supporting the notion that treatment with a combination of anti-VEGF, anti-IL8 and anti-IGF-1 antibodies can prevent the outgrowth of dormant cells even after DIRAS3 expression is lost, providing key insights into the mechanism of tumor dormancy and more importantly promoting translation of these finding to the clinic to treat dormant ovarian cancer cells.

Citation Format: Zhen Lu, Aaron F. Orozco, Margie Sutton, Wang Yan, Weiqun Mao, Robert Bast. IL8, VEGF and IGF-1 rescue ovarian cancer cells undergoing ARHI-mediated- autophagic cell death. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4987. doi:10.1158/1538-7445.AM2015-4987