Urokinase receptor promotes ovarian cancer cell dissemination through its 84-95 sequence

Katia Bifulco, Giuseppina Votta, Vincenzo Ingangi, Gioconda Di Carluccio, Domenica Rea, Simona Losito, Nunzia Montuori, Pia Ragno, Maria Patrizia Stoppelli, Claudio Arra, Maria Vincenza Carriero

Research output: Contribution to journalArticlepeer-review

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 (uPARΔD2D3) the 84-95 sequence. CHO-K1/D2D3 cells were able to cross matrigel, mesothelial and endothelial monolayers more efficiently than CHO-K1/ΔD2D3 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/ΔD2D3 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.

Original languageEnglish
Pages (from-to)4154-4169
Number of pages16
JournalOncotarget
Volume5
Issue number12
Publication statusPublished - 2014

Keywords

  • Cell invasion
  • Ovarian cancer
  • Urokinase receptor

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

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