CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion

Abstract

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.

Plasma endothelial protein C receptor influences innate immune response in ovarian cancer by decreasing the population of natural killer and TH17 helper cells

“…Our results indicate that aPC induces the secretion of cytokines such as TARC ( 23 , 24 ) , TECK ( 25 ) , IL-2 ( 26 ) , TPO ( 27 ) , BLC ( 28 ) , PDGF-BB ( 29 ) , CNTF (ciliary neurotrophic factor) ( 30 ) , I-TAC ( 31 ) and ICAM-3 ( 32 ) by tumor cells. These pleiotropic cytokines and proteins, believed to play a role in the development of T cells, are in addition chemoattractants for B and T lymphocytes.…”

Ovarian cancer molecular pathology

“…It has been established that chemokines such as CXCL12 induces migration, integrin expression, proliferation, and invasion [164]. CCL25-CCR9 interaction also contributes to ovarian cancer migration, metalloprotease expression, and invasion [165]. The hosting tissue is particularly important for metastasis efficiency since adipocytes of the omentum, which is a common site for ovarian tumor dissemination, can interact with the cells groups by adipokines such as IL8.…”

Intracellular expression profile and clinical significance of the CCR9–CCL25 chemokine receptor complex in nasopharyngeal carcinoma

“…[24][25][26][27][28] Further, CCR9 and its CCL25 ligand are overexpressed in prostate cancer cells of epithelial origin; the CCL25-CCR9 complex is important for prostate cancer invasion and metastasis. [32][33][34] In the present study, CCR9 and CCL25 protein localisation and expression, and CCR9 and CCL25 gene expression were determined in various nasopharyngeal carcinoma (NPC) stages using immunohistochemistry, Western blotting and quantitative reverse transcription polymerase chain reaction, respectively. In addition, CCL25 overexpression differentially modulated the expression of collagenase-1 and matrix metalloproteinase (MMP) 1, 2, 10, 11 and 13 in prostate cancer cells.…”