(2)卵巣癌の予後規程因子の同定とそれに基づく新たな分子標的治療の開発 : 腹膜播種の抑制に焦点を合わせて(<特集>第61回学術講演会シンポジウム3「卵巣癌の新たな治療戦略-基礎から,そして臨床から-」)

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Ovarian cancer has the highest mortality rate of all gynecologic tumors. It is often diagnosed at a late stage, after tumor cells are disseminated within the peritoneal cavity. A current working model for the metastatic process of ovarian carcinoma suggests that cancer cells are shed from the ovarian tumor into the peritoneal cavity and attach to the layer of mesothelial cells that line the inner surface of the peritoneum. The key process is the initial attachment to the peritoneal cavity, and inhibiting the attachment of ovarian cancer cells might give us new insights to treat ovarian cancer. E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that downregulation of E-cadherin would affect expression of cell-matrix adhesion receptors. Herein, we show that inhibition of E-cadherin in ovarian cancer cells causes upregulation of α_5-integrin expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently, which was inhibited by α_5β_1-integrin blocking antibody. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α_5-integrin, intraperitoneal treatment with an α_5β_1-integrin antibody significantly reduced tumor burden, ascites, number of metastasis. α_5-integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. 10 of 107 tissues (9%) had α_5-integrin overexpression and 39% had some level of α_5-integrin expression. The median survival for patients with high α_5-integrin levels was 26 months versus 35 months for these with low integrin expression (p<0.05). Taken together, we have identified α_5-integrin upregulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. Next, we focused on hepatocyte growth factor receptor, c-Met, a receptor tyrosine kinase that plays an important role in tumor growth by activating mitogenic signaling pathways and regulating adhesion and invasion. C-Met protein expression was detected by immunohistochemistry in 138 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. 15 of 138 tissues (11%) had c-Met overexpression. Median survival for patients with high c-Met levels was 17 months versus 32 months (p=0.001) for these with low c-Met expression. Infection of SKOV-3ip1 cells with an adenovirus expressing a siRNA against c-Met efficiently inhibited c-Met protein and mRNA expression. It also inhibited adhesion to different extracellular matrix components and human primary mesothelial cells. This was paralleled by a significant reduction in α5- and β1-integrin protein and mRNA expression. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with the c-Met siRNA significantly reduced tumor burden, ascites formation, protease activity, and the number of peritoneal implants. These results suggest that c-Met overexpression is a prognostic factor in ovarian cancer, and that targeting c-Met in vivo inhibits peritoneal dissemination and invasion through an α5β1-integrin dependent mechanism. Therefore, c-Met should be explored further as a therapeutic target in ovarian cancer. In ovarian cancer, despite current aggressive treatments, such as debulking surgical cytoreduction and intensive chemotherapy, more than two thirds of all patients succumb to the disease within 5 years. Presently used anticancer drugs, even if they are very effective at killing cancer cells, can be used only at limited concentrations because of their toxicity to normal cells. Accordingly, it seems worthwhile to look for drugs that inhibit the progression of ovarian cancer focusing on peritoneal dissemination. The mechanisms presented here may provide the basis for a novel clinical application that controls the metastasis of ovarian cancer in the near future.
社団法人日本産科婦人科学会の論文
2009-11-01

(2)卵巣癌の予後規程因子の同定とそれに基づく新たな分子標的治療の開発 : 腹膜播種の抑制に焦点を合わせて(<特集>第61回学術講演会シンポジウム3「卵巣癌の新たな治療戦略-基礎から,そして臨床から-」)

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