Expression of TREM‐1 in hepatic stellate cells and prognostic value in hepatitis B‐related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells (TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor-activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (sTREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM-1 from activated HSCs was observed after co-culture with HCC cell lines (P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM-1 significantly changed the migratory ability of HCC cells. The levels of sTREM-1 were significantly higher in patients with HCC than those with benign liver tumors (P < 0.005). Peritumoral density of TREM-1 was shown to be an independent prognosis predictor according to univariate (P < 0.001 for both overall survival and time to recurrence) and multivariate analysis (P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM-1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC. (Cancer Sci 2012; 103: 984-992) C ancer is characterized by complex tissues composed of multiple distinct cell types contributing to progressive development, metastatic dissemination, and high postoperative recurrence. Its progression is not just determined by cancer cells themselves, but also depends on various inflammatory cells recruited to tumor and stroma. (1,2) There is increasing evidence that various inflammatory cells are responsible for the tumor-promoting activities after seeding and establishment of metastatic cells. (3,4) Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy mainly triggered by exposure to hepatitis viral infection. (5) Therefore, inflammatory status has contributed to the extremely poor prognosis of HCC. Our previous results (6)(7)(8)(9) supported these connections by providing various inflammatory cells (such as activated hepatic stellate cells, macrophages, mast cells, and neutrophils) to discriminate populations of HCC with different survival outcomes. A unique peritumoral inflammatory/immune response signature of the liver microenvironment contributing to cancer metastatic propensity has also been linked to recurrence and metastasis of HCC, (10) suggesti...

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

“…The experimental protocols described in this study complied with the Ethics Review Committee of Zhongshan Hospital, Shanghai, China, and every patient provided written informed consent before enrollment. TMAs were constructed as previously described (Liao et al, 2012). All patients were monitored postoperatively until January 2012.…”

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

“…We did not detect differences in activation of caspase-1 and caspase-11 in TREM-1 knock-out macrophages suggesting that TREM-1 may not contribute to pyroptosis (38). Interestingly, recent studies have shown that TREM-1 is expressed in tumor-associated macrophages in colon, lung, and liver cancer and that the levels of TREM-1 expression correlate with the aggressiveness of tumor (19,21,22). The mechanisms by which TREM-1 contributes to tumor progression are not defined.…”

Chronic inflammation and cancer: emerging roles of triggering receptors expressed on myeloid cells

“…A separate study has confirmed elevated TREM-1 expression in human HCC cells [26]. High TREM-1 expression in tissue from HCC patients significantly correlates with poorer survival and serves as an independent prognostic factor for recurrence (HR = 1.58; 95% CI = 1.12– 2.24; P = 0.009).…”

“…While not extensively studied, TREM signaling could assume a significant role in such interplay (FIGURE 2). Indeed, TREM-1 is highly expressed in colon, hepatocellular and lung carcinoma tissues [14,26–28], and likely plays some role in cancer-associated inflammation and the tumor microenvironment.…”