CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling.
Ovarian cancer (OC) ascites consist in a proinflammatory tumor environment that is characterized by the presence of various cytokines, chemokines and growth factors. The presence of these inflammatory-related factors in ascites is associated with a more aggressive tumor phenotype. CCL18 is a member of CCL chemokines and its expression has been associated with poor prognosis in some cancers. However, its role in OC progression has not been established. Therefore, the aim of the current study was to elucidate the role of ascites CCL18 in OC progression.



ELISA and tissue microarrays were used to assess CCL18 in ascites and phospho-Pyk2 expression in cancer tissues respectively. Cell migration was assessed using Boyden chambers. CCL18 and ascites signaling was examined in ovarian cancer cells utilizing siRNA and exogenous gene expression.



Here, we show that CCL18 levels are markedly increased in advanced serous OC ascites relative to peritoneal effusions from women with benign conditions. Ascites and CCL18 dose-dependently enhanced the migration of OC cell lines CaOV3 and OVCAR3. CCL18 levels in ascites positively correlated with the ability of ascites to promote cell migration. CCL18 blocking antibodies significantly attenuated ascites-induced cell migration. Ascites and CCL18 stimulated the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) in CaOV3 and OVCAR3 cells. Most importantly, the expression of phosphorylated Pyk2 in serous OC tumors was associated with shorter progression-free survival. Furthermore, enforced expression of Pyk2 promoted tumor cell migration while siRNA-mediated downregulation of Pyk2 attenuated cell migration. Downregulation of Pyk2 markedly inhibited ascites and CCL18-induced cell migration.



Taken together, our findings establish an important role for CCL18, as a component of ascites, in the migration of tumor cells and identify Pyk2 as prognostic factor and a critical downstream signaling pathway for ascites-induced OC cell migration.
Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
Denis
D
Lane
Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
Isabelle
I
Matte
Département de Pathologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.
Claude
C
Laplante
Département de Pathologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.
Perrine
P
Garde-Granger
Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
Alex
A
Carignan
Service d'obstétrique et gynécologie, Département de Chirurgie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.
Paul
P
Bessette
Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.
Claudine
C
Rancourt
Département de Microbiologie et Infectiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada. alain.piche@usherbrooke.ca.
Alain
0000-0002-6313-4538
A
Piché
D001201:Ascites / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D019742:Chemokines, CC / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction
C111792:CCL18 protein, human; D019742:Chemokines, CC; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human
Ascites; CCL18; Cell migration; Ovarian carcinoma; Pyk2