title: CCL2 expression in primary ovarian carcinoma is correlated with chemotherapy response and survival outcomes.
abstract: CCL2, a chemokine, is expressed in normal human ovarian epithelium but down-regulated in ovarian adenocarcinomas. The association of CCL2 expression with chemotherapy response, invasion and survival outcomes was studied in patients with primary ovarian cancer (OC) and in ovarian cancer cell lines (OCCLs). Tumor specimens (>80% tumor) from patients with primary, advanced serous OC obtained at the time of cytoreductive surgery was used to isolate total RNA. The CCL2 gene expression evaluated by RT-PCR was investigated in relation to chemo-response/clinical outcomes in the OC patients and to sensitivity to cisplatin/paclitaxel in the OCCLs. In vitro invasion was measured by matrigel invasion and matrixmetallo-proteinase-9 (MMP-9) zymogram assays. Thirty-seven patients were included. In multivariable analyses that adjusted for the impact of debulking status, the CCL2 mRNA expression was correlated with objective complete response (p = 0.01), chemosensitivity (p = 0.04), and progression-free survival (PFS; p = 0.006). These findings were corroborated in vitro in the OCCLs. The cells expressing higher levels of CCL2 were more sensitive to paclitaxel and cisplatin as compared to those lines expressing lower levels of this chemokine. Up-regulation of CCL2 in the PAT-7 cell line further enhanced the response of these cells to paclitaxel (p = 0.0001) and led to decreased invasion (p = 0.0009). Increased ovarian tumoral expression of CCL2 is associated with improved chemoresponse and survival outcomes, and higher levels of CCL2 in ovarian cancer cell lines are associated with increased chemosensitivity and decreased invasion in vitro.
authors.affiliation: 2Department of Obstetrics and Gynecology, Taussig Cancer Institute, R40, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Amanda Nickles
authors.initials: AN
authors.lastname: Fader
authors.forename: Nabila
authors.initials: N
authors.lastname: Rasool
authors.forename: Susan A J
authors.initials: SA
authors.lastname: Vaziri
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kozuki
authors.forename: Pieter W
authors.initials: PW
authors.lastname: Faber
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Charles V
authors.initials: CV
authors.lastname: Biscotti
authors.forename: Chad M
authors.initials: CM
authors.lastname: Michener
authors.forename: Peter G
authors.initials: PG
authors.lastname: Rose
authors.forename: Luis
authors.initials: L
authors.lastname: Rojas-Espaillat
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Belinson
authors.forename: Mahrukh K
authors.initials: MK
authors.lastname: Ganapathi
authors.forename: Ram
authors.initials: R
authors.lastname: Ganapathi
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D012333:RNA, Messenger; D017239:Paclitaxel; D002945:Cisplatin