Versican enrichment predicts poor prognosis and response to adjuvant therapy and immunotherapy in gastric cancer

Abstract

BackgroundIncreasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on prognosis and the response to adjuvant therapy and immunotherapy in patients with gastric cancer (GC).MethodsFour independent cohorts containing 1353 patients with GC, were utilized to investigate the effect of VCAN expression on prognosis and response to adjuvant therapy in GC. Two cohorts treated with immune checkpoint blockades were included to assess the predict value of VCAN expression on response to immunotherapy. Moreover, the bulk RNA-seq and single-cell RNA-seq data were analyzed to illustrate the role of VCAN in tumor microenvironment. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves with the log-rank test.ResultHigh VCAN expression was associated with poor prognosis for patients with GC. Compared with patients with high VCAN expression, patients with low VCAN expression benefited more from adjuvant chemotherapy and adjuvant chemoradiotherapy. Moreover, patients with high VCAN expression tended to be resistant to immunotherapy, and VCAN could serve as a promising indicator for predicting the response to immunotherapy. VCANhigh tumors showed a specific microenvironment with more cancer associated fibroblasts infiltration and significant enrichment of stromal relevant signaling pathways.ConclusionVCAN could predict the response to adjuvant chemotherapy, adjuvant chemoradiotherapy and immunotherapy in GC, and designing new medicine target to VCAN might be an effective way to improve the efficacy of several treatment options for GC.

Tumor Purity-Related Genes for Predicting the Prognosis and Drug Sensitivity of DLBCL Patients

“…Conversely, its expression by stromal cells typically leads to a pro-inflammatory response [18]. In gastric cancer, high expression of VCAN has been associated with increased infiltration of fibroblasts, significant enrichment of stromal-associated signaling pathways and poor prognosis [19]. In hepatocellular carcinoma, VCAN exhibits a strong association with immune checkpoint gene expression [20].…”

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

“…HAPLN1 induced multi-drug resistance to bortezomib and ixazomib in patients with multiple myeloma [161]. GC patients with high VCAN are often resistant to immunotherapy [149]; in one study, cervical cancer patients who were resistant to chemotherapy also presented high expression of VCAN [162]. Similarly, elevated RHAMM expression in gliomas is correlated with worse clinical outcomes and higher risk of chemoresistance [163].…”

“…VCAN is widely expressed in the human body and imparts hygroscopic properties to the extracellular matrix (ECM), forming a loosely structured and hydrated matrix which is essential for supporting crucial processes in both development and disease [50]. Accumulation of VCAN in peritumoural stroma was associated with the prognosis of nodenegative breast cancer [142], early stage prostate cancer [143], NSCLC [144], oral squamous cell carcinoma [145], testicular germ cell tumours [146], cervical cancer [147], endometrial cancer [148], and epithelial ovarian cancer [149]. High VCAN expression was reported to be associated with poor prognosis in gastric cancer (GC) patients [149].…”

“…Accumulation of VCAN in peritumoural stroma was associated with the prognosis of nodenegative breast cancer [142], early stage prostate cancer [143], NSCLC [144], oral squamous cell carcinoma [145], testicular germ cell tumours [146], cervical cancer [147], endometrial cancer [148], and epithelial ovarian cancer [149]. High VCAN expression was reported to be associated with poor prognosis in gastric cancer (GC) patients [149].…”

Targets of tumor microenvironment for potential drug development

“…Versican, one of the chondroitin sulfate proteoglycan (CSPG) family members encoded by the VCAN gene, is engaged in cell adhesion, proliferation, migration, and angiogenesis. Song and colleagues demonstrated that high VCAN expression is related to the poor prognosis of patients with gastric cancer, and tumors exhibiting elevated VCAN expression are characterized by microenvironments featuring increased infiltration of CAFs and a notable enrichment of stromal related signaling pathways 226 . Kato and colleagues reported that VCAN secreted by CAFs promotes the carcinogenesis of hepatocellular carcinoma (HCC) cells, suggesting its potential as a novel therapeutic target 227 (Figure 4, right panel).…”