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...
B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19-2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.
Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target.
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