The Role of the Tumor Stroma in Ovarian Cancer

Abstract

The tumor microenvironment, consisting of stromal myofibroblasts, endothelial cells, and leukocytes, is growingly perceived to be a major contributor to the pathogenesis and disease progression in practically all cancer types. Stromal myofibroblasts produce angiogenic factors, proteases, growth factors, immune response-modulating proteins, anti-apoptotic proteins, and signaling molecules, and express surface receptors and respond to stimuli initiated in the tumor cells to establish a bi-directional communication network in the microenvironment to promote tumor cell invasion and metastasis. Many of these molecules are candidates for targeted therapy and the cancer stroma has been recently regarded as target for biological intervention. This review provides an overview of the biology and clinical role of the stroma in ovarian cancer.

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

“…The process is triggered by complex interactions of the tumor cells with the microenvironment and induction of diverse pathways (29)(30)(31). Crucial steps involve shedding of tumor cells from the primary tumor, development of resistance to anoikis, formation of multicellular aggregates (spheroids), transport by peritoneal fluid, implantation into the peritoneum by formation of mesothelial lining of pelvic and abdominal organs such as uterus and fallopian tubes, the omentum and the mesentery, and their growth as nodules (10,32).…”

“…In addition, they exhibit pronounced capacity to adhere to components of the ECM and mesothelial cells (37). Tumor cells in spheroids are also protected against antitumoral immune effector cells (29,30 (30). Interaction with mesenteric cells is essential for implantation in the peritoneum (18).…”

“…Endothelial cells are of importance for the metastatic process, as they promote the growth of metastases. After adherence, tumor cells penetrate the mesothelium and subsequently invade the underlying tissue, where they are able to induce angiogenesis as a prerequisite for growth and proliferation of tumor nodules (29)(30)(31). Crosstalk with immune cells by inactivation of immune effector cells through regulatory T-cells and due to other immunosuppressive mechanisms is another issue (29,30).…”

“…After adherence, tumor cells penetrate the mesothelium and subsequently invade the underlying tissue, where they are able to induce angiogenesis as a prerequisite for growth and proliferation of tumor nodules (29)(30)(31). Crosstalk with immune cells by inactivation of immune effector cells through regulatory T-cells and due to other immunosuppressive mechanisms is another issue (29,30). Tumor-associated macrophages have been identified as important contributors to metastasis, based on their shift from an antitumoral (M1) to a pro-tumoral (M2) subtype in ovarian cancer (40,41).…”

New Strategies in Ovarian Cancer: Translating the Molecular Complexity of Ovarian Cancer into Treatment Advances

“…Despite these negative results, drugs targeting the folate receptor remain of interest in ovarian cancer drug development given its high expression levels. In response to unique aspects of ovarian cancer, including the development of platinum resistance and the role of cancer stem cells and the tumor microenvironment, research efforts are leading to additional strategies for ovarian cancer (70,71). Studies of agents that have been shown to reverse platinum resistance in vitro are ongoing; recent negative trials of current agents, such as phenoxidiol and decitabine, have also brought up questions of which clinical settings are most appropriate for testing these agents (72,73).…”