Ovarian Cancer Development and Metastasis

Abstract

The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and upregulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia. (Am J Pathol

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

“…Data from four OCC cell lines silenced for CDCP1 expression and another overexpressing this protein demonstrated that CDCP1 mediates migration and spheroid formation in vitro, processes that are important for OCC in vivo. 7,8 Consistently, silencing of CDCP1 in TOV21G cells resulted in markedly lower tumor burden and accumulation of ascites in mice. In addition, TOV21G cells selected for high CDCP1 expression were able to induce 2.5-fold greater tumor burden and 5.8-fold more ascites in mice than TOV21G cells expressing this protein at~10-fold lower levels.…”

“…From samples obtained from mice killed on day 24, it was apparent that CDCP1 high cells were much more tumorigenic in vivo than CDCP1 low cells forming many more nodules on adipose tissue and the peritoneal membrane, and occasionally on the ovary, liver and spleen. Tumor nodules on the mesenteric 7,8 We noted above that modulation of CDCP1 has a marked impact on the ability of OCC cells to form spheres under non-adherent conditions (Figure 2g and Supplementary Figure S1d). To explore whether the role of CDCP1 in sphere formation promotes OCC, we selected populations of OCC cells that retain the ability to grow as spheres in long-term cell culture conditions by growing TOV21G and KOC7C cells in ultra-low-attachment plates in complete media.…”

“…In contrast with the other tumor types, which generally employ the vasculature to spread to distant sites, hematogenous metastases are rarely present at diagnosis of epithelial ovarian cancer. 7,8 Instead epithelial ovarian cancer metastasis occurs via intraperitoneal dissemination, a process characterized by direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. During these processes survival of malignant cells is promoted via non-adherent growth as spheroids.…”

“…These multicellular structures also facilitate attachment to, and invasion into the mesothelium of abdominal organs and the omentum. 7,8 Currently, the molecular mechanisms orchestrating these processes are uncertain; in particular, the signaling pathways used by malignant cells to survive anchoragefree stress and colonize remote sites are poorly defined. Understanding these events at the molecular level is likely to provide new opportunities to therapeutically target ovarian cancer.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…Overall survival rates for the two types differ dramatically, with median survival being 82 months [4] versus 30 months [5] for Types I and II, respectively. This difference is despite the initial sensitivity of type II tumours to standard carboplatin and paclitaxel chemotherapy.…”