PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4

Abstract

Ovarian cancer is the leading cause of death among all the gynecological cancers in the United States. Ovarian cancer employs a unique mode of metastasis, as exfoliated tumor cells disseminate within the peritoneal cavity, colonizing in several sites as well as accumulating ascites. Tumor recurrence and widespread metastasis are significant factors contributing to poor prognosis. PRSS21 is a metastasis associated ovarian cancer gene that encodes the glycosylphosphatidylinositol-linked serine protease, testisin. Testisin expression is increased in multiple ovarian tumor types, with relatively little expression in normal tissues, but is differentially decreased in metastatic ovarian serous carcinomas compared to primary tumors. Here we explored the function of testisin in late stage ovarian cancer progression using a murine xenograft model of ovarian intraperitoneal tumor metastasis. Increased tumor testisin expression inhibited intraperitoneal tumor seeding and colonization, ascites accumulation, and metastatic tumor burden that was dependent on catalytically active testisin. The known testisin substrate, protease activated receptor-2 (PAR-2) is a target of testisin activity. Gene profiling and mechanistic studies demonstrate that testisin activity suppresses the synthesis and secretion of pro-angiogenic angiopoietins, ANG2 and ANGPTL4, which normally promote vascular leak and edema. These observations support a model wherein testisin activates PAR-2 to antagonize proangiogenic angiopoietins that modulate vascular permeability and ascites accumulation associated with ovarian tumor metastasis.

Deregulation of angiopoietin-like 4 slows ovarian cancer progression through vascular endothelial growth factor receptor 2 phosphorylation

“…Silencing ANGPTL4 reduces A2780 and CAOV3 tumor growth, angiogenesis, and metastasis in vivo but not in vitro, indicating that ANGPTL4 is essential for tumor proliferation and vascular angiogenesis in ovarian cancer. However, several studies have claimed that ANGPTL4 inhibits vascular angiogenesis and prevents tumor metastasis in melanoma B16F0, lung cancer 3LL [ 10 ] and colon cancer CMT93 [ 9 ] xenograft mouse models; however, contrasting results were observed in breast cancer [ 11 ], renal cell carcinoma [ 14 ], and ovarian cancer [ 16 , 17 ] xenograft models, indicating that ANGPTL4 may act as a tissue-specific and multifunctional vascular modulator. Furthermore, previous studies have shown that two proteins, PDZ-binding motif (TAZ) and testisin, inhibit ovarian cancer metastasis and that ferroptosis and chemoresistance are also related to ANGPTL4 inhibition [ 16 , 27 ].…”

“…In addition, the transforming growth factor-beta 2 (TGF-β2)/ANGPTL4 axis was reported to be responsible for breast cancer brain metastasis in a mouse model [ 15 ]. Previous studies reported that high ANGPTL4 expression was detected in ovarian cancer xenograft mouse models and patients and was associated with shorter relapse-free survival times in serous ovarian carcinoma [ 16 , 17 ]. However, whether ANGPTL4 deletion has clinical benefit in ovarian cancer therapy is unknown, and the related molecular mechanisms are obscure.…”

Identification of a Glycolysis-Related Gene Signature for Survival Prediction of Ovarian Cancer Patients

“…[49] Moreover, large amounts of it has been detected in malignant ascites of serous OV patients. [50] High ANGPTL4 levels predict shorter relapse-free survival in serous OV. [50,51] Studies have found that high promoter hypermethylation of TGFBI (transforming growth factor-beta-inducible gene) is involved in chemotherapy resistance of paclitaxel in OV.…”

Identification of a Glycolysis-Related Gene Signature for Survival Prediction of Ovarian Cancer Patients

“…(50) High ANGPTL4 levels predict shorter relapse-free survival in serous OV. (50,51) Studies have found that high promoter hypermethylation of TGFBI (transforming growth factor-beta-inducible gene) is involved in chemotherapy resistance of paclitaxel in OV. (52,53) A study showed that TGFBI and periostin, predict poor prognosis in serous epithelial OV.…”