title: Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis.
abstract: Inflammatory cells play important roles in progression of solid neoplasms including ovarian cancers. Tumor-associated macrophages (TAMs) contribute to angiogenesis and immune suppression by modulating microenvironment. Ovarian cancer develops occasionally on the bases of endometriosis, a chronic inflammatory disease. We have recently demonstrated differential expressions of CXCR3 variants in endometriosis and ovarian cancers. In this study, we showed impaired CXCL4 expression in TAMs of ovarian cancers arising in endometriosis. The expressions of CXCL4 and its variant CXCL4L1 were investigated among normal ovaries (n = 26), endometriosis (n = 18) and endometriosis-associated ovarian cancers (EAOCs) composed of clear cell (n = 13) and endometrioid (n = 11) types. In addition, four cases of EAOCs that contained both benign and cancer lesions contiguously in single cysts were investigated in the study. Western blot and quantitative RT-PCR analyses revealed significant downregulation of CXCL4 and CXCL4L1 in EAOCs compared with those in endometriosis. In all EAOCs coexisting with endometriosis in the single cyst, the expression levels of CXCL4 and CXCL4L1 were significantly lower in cancer lesions than in corresponding endometriosis. Histopathological study revealed that CXCL4 was strongly expressed in CD68 (+)  infiltrating macrophages of endometriosis. In microscopically transitional zone between endometriosis and EAOC, CD68 (+)  macrophages often demonstrated CXCL4 (-)  pattern. The majority of CD68 (+)  TAMs in overt cancer lesions were negative for CXCL4. Collective data indicate that that CXCL4 insufficiency may be involved in specific inflammatory microenvironment of ovarian cancers arising in endometriosis. Suppression of CXCL4 in cancer lesions is likely to be attributable to TAMs in part.
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. mfuruya@yokohama-cu.ac.jp
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Etsuko
authors.initials: E
authors.lastname: Miyagi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kami
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nagahama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Fumiki
authors.initials: F
authors.lastname: Hirahara
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inayama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
mesh_terms: D000328:Adult; D000368:Aged; D004715:Endometriosis / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D010978:Platelet Factor 4 / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport
chemical_list: C064936:PF4V1 protein, human; D010978:Platelet Factor 4