TY - JOUR
T1 - The inflammatory microenvironment in epithelial ovarian cancer
T2 - a role for TLR4 and MyD88 and related proteins
AU - Li, Zheng
AU - Block, Matthew S.
AU - Vierkant, Robert A.
AU - Fogarty, Zachary C.
AU - Winham, Stacey J.
AU - Visscher, Daniel W.
AU - Kalli, Kimberly R.
AU - Wang, Chen
AU - Goode, Ellen L.
N1 - Publisher Copyright:
© 2016, International Society of Oncology and BioMarkers (ISOBM).
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
KW - Endogenous ligands
KW - Epithelial ovarian cancer
KW - Myeloid differentiation primary response gene eighty-eight (MyD88)
KW - NF-κB signaling pathway
KW - Toll-like receptor four (TLR4)
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U2 - 10.1007/s13277-016-5163-2
DO - 10.1007/s13277-016-5163-2
M3 - Article
C2 - 27460076
AN - SCOPUS:84979663880
SN - 1010-4283
VL - 37
SP - 13279
EP - 13286
JO - Tumor Biology
JF - Tumor Biology
IS - 10
ER -