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Differential roles of uPAR in peritoneal ovarian carcinomatosis.

ABSTRACT: Epithelial ovarian cancer is the fourth leading cause of death from gynecologic malignancies in the United States. Most cases are diagnosed at late stages, with the solid tumor masses growing as peritoneal implants, or floating within the ascitic fluid (peritoneal ovarian carcinomatosis). Despite aggressive surgical "debulking," recurrence of recalcitrant disease is frequent with poor patient survival. Efforts to improve survival rates are hindered by lack of biomarkers that can detect and effectively treat ovarian cancer in its early stages. Urokinase plasminogen activator receptor (uPAR) is a multifunctional receptor involved in a myriad of tumor cell processes. However, the role of host uPAR in ovarian cancer is still elusive. To define the potential proinflammatory role of uPAR in ovarian cancer, first, using a syngeneic murine model in uPAR(-/-) mice, we found that ablation of uPAR restrained tumor take and peritoneal implants and prolonged the survival of uPAR(-/-) mice compared with their uPAR(+/+) counterparts. Ascitic fluid accumulation was significantly decreased in uPAR(-/-) mice with decreased macrophage infiltration. Second, in vitro mechanistic studies revealed that host uPAR is involved in the multiple steps of peritoneal metastatic cascade. Third, we evaluated the prognostic utility of tumor and stromal uPAR in human ovarian cancer tissue microarray. In summary, our studies indicated that uPAR plays a significant role in ovarian cancer cell-stromal crosstalk and contributes to increased vascular permeability and inflammatory ovarian cancer microenvironment. This provides a rationale for targeting the uPAR with either specific neutralizing antibodies or targeting its downstream inflammatory effectors in patients with ovarian cancer.

SUBMITTER: Al-Hassan NN

PROVIDER: S-EPMC3349253 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Differential roles of uPAR in peritoneal ovarian carcinomatosis.

Al-Hassan Nada N NN Behzadian Ali A Caldwell Ruth R Ivanova Vessela S VS Syed Viqar V Motamed Kouros K Said Neveen A NA

Neoplasia (New York, N.Y.) 20120401 4

Epithelial ovarian cancer is the fourth leading cause of death from gynecologic malignancies in the United States. Most cases are diagnosed at late stages, with the solid tumor masses growing as peritoneal implants, or floating within the ascitic fluid (peritoneal ovarian carcinomatosis). Despite aggressive surgical "debulking," recurrence of recalcitrant disease is frequent with poor patient survival. Efforts to improve survival rates are hindered by lack of biomarkers that can detect and effec ...[more]

PMID: 22577342

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Project description:PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

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Differential roles of uPAR in peritoneal ovarian carcinomatosis.

Publications

Differential roles of uPAR in peritoneal ovarian carcinomatosis.

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