Death rates attributable to ovarian cancer have been largely unchanged for decades. Although the initial response of ovarian cancer to surgical debulking and chemotherapy with platinum-based drugs and taxanes is often excellent, relapse with drug-resistant cancer usually occurs and patients succumb to their disease. Unfortunately, most women diagnosed with ovarian cancer present with advanced stage cancer, and for these women, current therapy is largely palliative rather than curative. Given our failure to improve long-term survival from ovarian cancer despite our best efforts with currently available (largely conventional) therapies, there is a great need to understand from a novel angle the specific cellular and molecular mechanisms by which chemoresistance occurs and tumor relapses in patients with ovarian cancer. The tumor microenvironment is comprised of tumor cells, tumor initiating cells (or cancer stem cells, CSC), and immune cells (e.g. myeloid derived suppressor cells, MDSC). CSCs are thought to play critical roles in tumor initiation, metastasis and therapeutic resistance. The mechanisms controlling the self-renewal and expansion of CSCs are poorly understood in ovarian cancer. We hypothesized that immunosuppressive cells (e.g. MDSC) play a crucial role in regulating CSC self-renewal and expansion and controlling chemotherapy resistance and tumor relapse. Our preliminary studies have demonstrated significant MDSC infiltration within fresh tumor tissue harvested from patients with ovarian cancer. These MDSCs are able to inhibit T cell immunity. Ovarian cancer associated MDSCs released nitrite oxide (NO) and activated Notch/Bcl signaling pathway, and linked to chemoresistance. Furthermore, MDSCs stimulated microRNA101, targeted C-terminal binding protein-2 (CtBP2)/core stem cell gene signaling pathway and impact ovarian cancer stemness. Thus, an immune suppressive mechanism may significantly impact ovarian cancer biology and therapy.
Our specific aims are:
Aim 1 : To test our hypothesis that MDSCs affect ovarian cancer stemness, chemotherapy and outcome.
Aim 2 : To test our hypothesis that MDSCs target Notch/BCL signaling and affect cancer chemoresistance.
Aim 3 : To test our hypothesis that MDSCs target microRNA/CtBP2 and affect ovarian cancer stemness. The proposal investigates a real human disease, links tumor immunology to tumor stem cell biology, tumor biology and chemotherapy, and addresses the mechanistic associations between tumor immune suppression and cancer stem cell self-renewal in the tumor environment, and tackles a significant clinical problem. The proposal is highly scientifically and clinically significant and ill pave the way for novel clinical trials in the field.
Given our failure to improve long-term survival from ovarian cancer despite our best efforts with currently available (largely conventional) therapies, there is a great need to understand from a novel angle the specific cellular and molecular mechanisms by which chemoresistance occurs and tumor relapses in patients with ovarian cancer. The tumor microenvironment is comprised of tumor cells, immune cells (e.g. myeloid derived suppressor cells, MDSC) and tumor initiating cells (or cancer stem cells). It is well defined that MDSCs play detrimental roles in tumor immunity in tumor bearing mouse models. However, the nature of MDSCs is poorly understood in human ovarian cancer microenvironment. It is assumed that ovarian cancer associated MDSCs inhibit T cell immunity. In addition to their potential immune suppressive roles, it is unknown whether and how MDSCs affect tumor progression, relapse and chemoresistance in human ovarian cancer. In this application we focus on the interaction between MDSCs and cancer cells in patients with ovarian cancer, and explore the cellular and molecular mechanisms by which control cancer stem cell renewal and expansion, and chemoresistance. The application is conceptually and applicably significant, and will generate novel insight into new approaches in cancer immune and chemotherapy.
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