Abstract
The clinical relevance of the urokinase receptor (uPAR) as a prognostic marker in ovarian cancer is well documented. We had shown that the uPAR sequence corresponding to 84-95 residues, linking D1 and D2 domains (uPAR84-95), drives cell migration and angiogenesis in a protease-independent manner. This study was aimed at defining the contribution of uPAR84-95 sequence to invasion of ovarian cancer cells. Now, we provide evidence that the ability of uPAR-expressing ovarian cancer cells to cross extra-cellular matrix and mesothelial monolayers is prevented by specific inhibitors of the uPAR84-95 sequence. To specifically investigate uPAR84-95 function, uPAR-negative CHO-K1 cells were stably transfected with cDNAs coding for uPAR D2 and D3 regions exposing (uPARD2D3) or lacking (uPAR∆D2D3) the 84-95 sequence. CHO-K1/D2D3 cells were able to cross matrigel, mesothelial and endothelial monolayers more efficiently than CHO-K1/∆D2D3 cells, which behave as CHO-K1 control cells. When orthotopically implanted in nude mice, tumor nodules generated by CHO-K1/D2D3 cells spreading to peritoneal cavity were more numerous as compared to CHO-K1/∆D2D3 cells. Ovarian tumor size and intra-tumoral microvessel density were significantly reduced in the absence of uPAR84-95. Our results indicate that cell associated uPAR promotes growth and abdominal dissemination of ovarian cancer cells mainly through its uPAR84-95 sequence.
Highlights
Epithelial ovarian carcinoma (EOC) is a highly lethal tumor due to its propensity to form widespread peritoneal implants throughout the abdominal cavity
Using human ovarian carcinoma SKOV-3 cells expressing uPAR, hamster ovarian CHO-K1 cells lacking uPAR and stably transfected with cDNAs coding for GPI-anchored, truncated forms of uPARs lacking the N-terminal D1 domain and exposing or lacking the 84–95 sequence, we investigated whether the presence, or the deletion of uPAR84–95 plays a role in the growth and intrawww.impactjournals.com/oncotarget abdominal dissemination of ovarian cells orthotopically implanted in nude mice
This work was aimed to identify the specific contribution of the uPAR84-95 region in promoting dissemination of ovarian cancer cells bearing GPIanchored uPAR
Summary
Epithelial ovarian carcinoma (EOC) is a highly lethal tumor due to its propensity to form widespread peritoneal implants throughout the abdominal cavity. The metastatic potential of tumor cells depends on many factors, including the ability to cross physical barriers and to interact with the microenvironment at the metastatic site, in turn promoting cell adhesion, growth, survival, angiogenesis, and invasion [1,2,3,4]. Ovarian cancer cells detach from the primary tumor and float in the ascitic fluid as single cells or multicellular, chemoresistant spheroids which spread throughout the peritoneal cavity where they adhere and invade through the mesothelium. Understanding the molecular mechanisms by which ovarian cancer cells adhere to the mesothelium www.impactjournals.com/oncotarget and/or transmigrate through microvessels is a prerequisite to the development of new prognostic tools as well as strategies to limit intra-abdominal tumor dissemination
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