Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Abstract

Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-β (TGFβ) signaling. Platelet-derived growth factor receptor β (PDGFRβ), which is a receptor tyrosine kinase and is also a downstream signal of TGFβ, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRβ and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFβ treatment in the colon cancer cell line DLD-1. TGFβ and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRβ blockade. We propose that the PDGFRβ signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRβ signaling due to increased TGFβ and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.

Pathological Significance and Prognostic Roles of Thrombospondin-3, 4 and 5 in Bladder Cancer

“…However, several investigators have reported that TSP-4 exerts pro-angiogenic activities in tissue remodeling and tendinopathy development (49,50). Similar pro-angiogenic activities of TSP-4 have been reported through in vivo and in vitro studies on breast cancer and colorectal cancer (51,52).…”

Extracellular Matrix Biomarkers in Colorectal Cancer

“…Recently, it was found that there are increased levels of THBS4 in colorectal cancer patients and it is highly associated with PDGFRβ expression in tumor tissues compared to normal tissues [20]. Further, the expression level of THBS4 was also significantly increased with increased expression of PDGFRβ, despite no significant changes in mRNA [20].…”

“…MMP and LOX promote collagen degradation and cross-linking, respectively [18,19]. Recently, we found increased levels of THBS4, an ECM protein, is highly associated with PDGFRβ expression in tumor tissues when compared to normal tissues of colon cancer patients [20].…”

Identification Hub Genes of Consensus Molecular Subtype Correlation With Immune Infiltration and Predict Prognosis in Gastric Cancer

“…As a secreted extracellular matrix protein, THBS4 has been reported mediated angiogenesis responding to TGF-β signaling [37]. THBS4 in favor of an oncogene in colorectal cancer [38], prostate cancer [39], and hepatocellular carcinoma [40]. Compared to normal tissues, THBS4 expression at a higher level in those cancers.…”

“…Compared to normal tissues, THBS4 expression at a higher level in those cancers. In colorectal cancer, THBS4 secretion induced by TGFβ/ PDGFRβ pathways and promoted adhesion, migration, and proliferation of colorectal cancer [38]. And THBS4 might as a potential therapeutic target in prostate cancer, inhibited expression of THBS4 could impede the PI3K/Akt signaling and disturb the cancer stem cell (CSC)-like properties [39].…”