Abstract
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg Cancer Res; 78(9); 2305-17. ©2018 AACR.
Highlights
Abundant macrophage infiltration is a common feature of tumors [1, 2]
The data showed that the mRNA levels of SPON2 in hepatocellular carcinoma (HCC) tissues were higher than that in the corresponding noncancerous liver (CNL) tissues (Supplementary Fig. S1A)
The results showed that blocking integrin a5 and b1 abrogated the inhibitory effects of SPON2 on HCC cell migration (Fig. 4C)
Summary
Abundant macrophage infiltration is a common feature of tumors [1, 2]. M1 or M2 subtype represents tumor suppressive or tumor-supportive macrophages, respectively. Specific tumor microenvironmental signals further determine the polarization and functions of macrophages [3]. For many solid tumor types, a high density of cells expressing macrophage-associated markers is generally associated with a poor clinical outcome [4]. Conflicting data exist for lung, stomach, prostate, and bone malignancies, where both positive and negative outcome associations with increased macrophage density have been detected. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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