Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

• Published in: Oncogene Vol. 36; no. 2; pp. 168 - 181
• Main Authors: Saini, Uksha, Naidu, Shan, ElNaggar, Adam C, Bid, Hemant Kumar, Wallbillich, John J, Bixel, Kristin, Bolyard, Chelsea, Suarez, Adrian A, Kaur, Balveen, Kuppusamy, Periannan, Hays, John, Goodfellow, Paul J, Cohn, David E, Selvendiran, Karuppaiyah
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 12.01.2017
• Subjects: Angiogenesis; Animals; Ascites; Ascites - metabolism; Ascites - pathology; Cancer metastasis; Care and treatment; Cell Movement; Chemotherapy; Development and progression; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockout Techniques; Genes; Genetic aspects; Health aspects; Humans; Inhibitor drugs; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Piperidones - administration & dosage; Piperidones - pharmacology; Signal Transduction - drug effects; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Up-Regulation - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.197

Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.