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A role for paracrine interleukin‐6 signaling in the tumor microenvironment in prostate tumor growth
Author(s) -
Yu ShuHan,
Maynard Janielle P.,
Vaghasia Ajay M.,
De Marzo Angelo M.,
Drake Charles G.,
Sfanos Karen S.
Publication year - 2019
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23726
Subject(s) - tramp , paracrine signalling , stromal cell , tumor microenvironment , prostate cancer , prostate , cancer research , tumor progression , pathology , medicine , cancer , biology , receptor
Background Interleukin‐6 (IL‐6) is a mediator of inflammation that can facilitate prostate cancer progression. We previously demonstrated that IL‐6 is present in the prostate tumor microenvironment and is restricted almost exclusively to the stromal compartment. The present study examined the influence of paracrine IL‐6 signaling on prostate tumor growth using allograft models of mouse prostate cancer (TRAMP‐C2), colon cancer (MC38), and melanoma (B16) cell lines in wildtype (WT) and IL‐6 knockout (IL‐6 −/− ) mice. Methods Cells were implanted into WT or IL‐6 −/− mice and tumor sizes were measured at a 3 to 4 day interval. Serum, tumors, and other organs were collected for IL‐6 analysis by ELISA and RNA in situ hybridization (RISH). Results There was a significant reduction in TRAMP‐C2 and B16 tumor size grown in IL‐6 −/− mice versus WT mice ( P = 0.0006 and P = 0.02, respectively). This trend was not observed for the MC38 cell line. RISH analysis of TRAMP‐C2 tumors grown in WT mice showed that cells present in the tumor microenvironment were the primary source of IL‐6 mRNA, not the TRAMP‐C2 cells. Serum IL‐6 ELISA analyses showed an increase in the circulating levels of IL‐6 in WT mice bearing TRAMP‐C2 tumors. Similar phospho‐STAT3 expression and tumor vascularization were observed in TRAMP‐C2 tumors grown in WT and IL‐6 −/− mice. Conclusions Our results are consistent with previous studies in prostate cancer patients demonstrating that paracrine IL‐6 production in the tumor microenvironment may influence tumor growth. Additionally, these data provide evidence that elevated systemic IL‐6 levels may be involved in tumor growth regulation in prostate cancer, and are not simply caused by or indicative of tumor burden.