Targeting an autocrine IL-6–SPINK1 signaling axis to suppress metastatic spread in ovarian clear cell carcinoma

Targeting an autocrine IL-6–SPINK1 signaling axis to suppress metastatic spread in ovarian clear cell carcinoma

Women diagnosed with ovarian cancer face an average 5 year survival rate of only 46%; low survival is driven by early and ongoing intraperitoneal spread of tumor cells. Patients often experience formation of malignant ascites, fluid formation within the abdominal cavity that contains tumor cells. Over time, the tumor cells form thousands of tumor nodules on the surface of all the abdominal organs, leading to bowel blockages and compromising the functions of vital organs. To date there are inadequate therapeutic options for these patients of whom about 70% will experience this form of metastasis during the course of their disease.

Ovarian cancer represents a number of different subtypes. In this study, our interest is specifically on the ovarian clear cell carcinoma (OCCC) subtype that has a particularly poor prognosis when diagnosed in later stage, as these tumors tend to be treatment resistant, leaving no effective therapeutic options.

A prerequisite for tumors to metastasize is to be unresponsive to cell death protocols which are normally induced due to loss of cell attachment (this is termed anoikis resistance). In our work we seek to better understand the mechanisms involved in anoikis resistance in OCCC and subsequently identify new therapeutic strategies for these women to increase overall survival.

In our study we have found that Serine Protease Inhibitor Kazal type 1 (SPINK1), an endogenous inhibitor of trypsin-like serine proteases, is also an important regulator of anoikis resistance in OCCC. We have established a novel intraperitoneal metastatic OCCC mouse model where the tumors establish themselves on the internal organs. We show here that silencing of the SPINK1 gene significantly reduced metastatic lesions. Furthermore, we identified that tumor cell expressed interleukin 6 (IL6) increases tumor cell expression of SPINK1 through autocrine signaling. Our investigation included the evaluation of the IL6 receptor  inhibitor Tocilizumab, and we showed that in vitro drug treatment reduces tumor cell survival, while in vivo drug treatment produces a significant reduction of metastatic lesions in peritoneal organs, as well as a reduction of tumor associated ascites. 

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This study may be a first step towards better understanding of anoikis resistance, a critical component of ovarian cancer progression and metastasis, and may lead towards identifying novel therapeutic targets and therapeutic approaches specifically for women with OCCC.

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