title: The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins.
abstract: The tumor-associated inflammatory microenvironment may play a pivotal role in epithelial ovarian cancer (EOC) carcinogenesis and outcomes, but a detailed profile in patient-derived tumors is needed. Here, we investigated the expression of TLR4- and MyD88-associated markers in tumors from over 500 EOC patients using immunohistochemical staining. We demonstrate that high expression of TLR4 and MyD88 predicts poorer overall survival in patients with EOC; most likely, this is due to their association with serous histology and features of high tumor burden and aggressiveness, including stage, grade, and ascites at surgery. Combined TLR4 and MyD88 expression appears to serve as an independent risk factor for shortened survival time, even after covariate adjustment (both moderate HR 1.1 [95 % CI 0.7-1.8], both strong HR 2.1 [95 % CI 1.1-3.8], both weak as referent; p = 0.027). We reveal that in EOC tissues with elevated expression of both TLR4 and MyD88 and activated NF-κB signaling pathway, expression of hsp60, hsp70, beta 2 defensin, and HMGB1 are also enriched. In total, these results suggest that activation of TLR4/MyD88/NF-κB signaling by endogenous ligands may contribute to an inflammatory microenvironment that drives a more aggressive phenotype with poorer clinical outcome in EOC patients.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Block
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Fogarty
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Winham
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D000077216:Carcinoma, Ovarian Epithelial; D002471:Cell Transformation, Neoplastic; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D020780:Matrix Metalloproteinase 9
keywords: Endogenous ligands; Epithelial ovarian cancer; Myeloid differentiation primary response gene eighty-eight (MyD88); NF-κB signaling pathway; Toll-like receptor four (TLR4)