The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer

Abstract

IntroductionThrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC).Materials and methodsWe retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.ResultsTHBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.ConclusionTHBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.

Diagnostic, Therapeutic, and Prognostic Value of the Thrombospondin Family in Gastric Cancer

“…Heat maps in Oncomine presented that the color in the diffuse type was darker than the intestinal type, in accordance with the previous study (Förster et al, 2011). Kuroda et al showed that it was cancer-associated fibroblasts (CAFs) rather than normal-associated fibroblasts that expressed THBS4, and high expression of THBS4 was correlated with larger tumor size, more aggressiveness, lymph node metastasis, and poor OS, which was similar to our findings (Kuroda et al, 2019). Research studying the mechanism of THBS4 in GC is rare, and in endothelial cells, TGF-β1 can upregulate the THBS4 expression and affect angiogenesis, contributing to tumor growth (Muppala et al, 2017).…”

Gastric cancer: a comprehensive review of current and future treatment strategies

“…Thrombospondin-4, a cell-cell and cell-matrix interaction promoting protein, was found to be expressed within stromal cells absent of cytokeratin expression, which correlated with higher invasion, metastasis, and worse overall outcome clinically [103]. IL-6, a pro-inflammatory cytokine that is excreted in the CAFs via tumor stroma, progresses gastric cancer through JAK2/STAT3 signaling pathway, enhances epithelial-to-mesenchymal transition (EMT) and migration of gastric cancer cells [104]. Lactic acid, a secondary metabolite found as a byproduct of the Warburg effect, has been shown to promote macrophage polarization through angiogenic signaling via HIF1a and is highly prominent within the gastric cancer microenvironment [105].…”

Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma

“…The stroma-rich subtype, had the highest level of stroma signature score. Genes known to be associated with stromal content and cancer-associated fibroblasts (THBS4, CNTN1, CXCL14 and BOC) [77][78][79][80] were differentially expressed (Fig. 5).…”