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Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium.

ABSTRACT: Mucin16 [MUC16/cancer antigen 125 (CA-125)], a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further, when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP, surface expression of MUC16/CA-125 was lost, whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence, decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless, meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together, these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding, reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However, proteolytic clearing of MUC16/CA-125, catalyzed by MT1-MMP, may then expose integrins for high-affinity cell binding to peritoneal tissues, thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.

SUBMITTER: Bruney L

PROVIDER: S-EPMC5568695 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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Project description:BackgroundOvarian carcinoma (OvCa) is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells and its only natural ligand, CCL25, is largely expressed in the thymus, which involutes with age. Other than the thymus, CCL25 is expressed by the small bowel. Interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for OvCa cells. The current study shows OvCa tissue and cells significantly express CCR9, which interacts with CCL25 to support carcinoma cell migration and invasion.MethodsRT-PCR and flow cytometry techniques were used to quantify the expression CCR9 by OvCa cells. OvCa tissue microarrays (TMA) was used to confirm CCR9 expression in clinical samples. The Aperio ScanScope scanning system was used to quantify immunohistochemical staining. Cell invasion and migration assays were performed using cell migration and matrigel invasion chambers. Matrix metalloproteinase (MMP) mRNAs were quantified by RT-PCR and active MMPs were quantified by ELISA.ResultsOur results show significantly (p<0.001) higher expression of CCR9 by mucinous adenocarcinoma, papillary serous carcinoma, and endometriod ovarian carcinoma cases, than compared to non-neoplastic ovarian tissue. Furthermore, CCR9 expression was significantly elevated in OvCa cell lines (OVCAR-3 and CAOV-3) in comparison to normal adult ovarian epithelial cell mRNA. OvCa cells showed higher migratory and invasive potential towards chemotactic gradients of CCL25, which was inhibited by anti-CCR9 antibodies. Expression of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), and stromelysins (MMP-3, -10, and -11) by OvCa cells were modulated by CCL25 in a CCR9-dependent fashion.ConclusionsThese results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.

Project description:ImportanceA 2009 randomized clinical trial demonstrated that using cancer antigen 125 (CA-125) tests for routine surveillance in ovarian cancer increases the use of chemotherapy and decreases patients' quality of life without improving survival, compared with clinical observation. The Society of Gynecologic Oncology guidelines categorize CA-125 testing as optional and discourage the use of radiographic imaging for routine surveillance. To date, few studies have examined the use of CA-125 tests in clinical practice.ObjectivesTo examine the use of CA-125 tests and computed tomographic (CT) scans in clinical practice before and after the 2009 randomized clinical trial and to estimate the economic effect of surveillance testing.Design, setting, and participantsA prospective cohort of 1241 women with ovarian cancer in clinical remission after completion of primary cytoreductive surgery and chemotherapy at 6 National Cancer Institute-designated cancer centers between January 1, 2004, and December 31, 2011, was followed up through December 31, 2012, to study the use of CA-125 tests and CT scans before and after 2009. Data analysis was conducted from April 9, 2014, to March 28, 2016.Main outcomes and measuresThe use of CA-125 tests and CT scans before and after 2009. Secondary outcomes included the time from CA-125 markers doubling to retreatment among women who experienced a rise in CA-125 markers before and after 2009, and the costs associated with surveillance testing using 2015 Medicare reimbursement rates.ResultsAmong 1241 women (mean [SD] age 59 [12] years; 1112 white [89.6%]), the use of CA-125 testing and CT scans was similar during the study period. During 12 months of surveillance, the cumulative incidence of patients undergoing 3 or more CA-125 tests was 86% in 2004-2009 vs 91% in 2010-2012 (P = .95), and the cumulative incidence of patients undergoing more than 1 CT scan was 81% in 2004-2009 vs 78% in 2010-2012 (P = .50). Among women whose CA-125 markers doubled (n = 511), there was no significant difference in the time to retreatment with chemotherapy before and after 2009 (median, 2.8 vs 3.5 months; P = .40). During a 12-month period, there was a mean of 4.6 CA-125 tests and 1.7 CT scans performed per patient, resulting in a US population surveillance cost estimate of $1 999 029 per year for CA-125 tests alone and $16 194 647 per year with CT scans added.Conclusions and relevanceCA-125 tests and CT scans are still routinely used for surveillance testing in patients with ovarian cancer, although their benefit has not been proven and their use may have significant implications for patients' quality of life as well as costs.

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Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium.

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