1462

VCAN

versican;VCAN;versican

chondroitin sulfate proteoglycan 2|chondroitin sulfate proteoglycan core protein 2|glial hyaluronate-binding protein|large fibroblast proteoglycan|versican core protein|versican proteoglycan

5q14.3

protein-coding

Sialylation is one of the altered protein glycosylations associated with cancer development. The sialoglycoproteins in cancer cells, however, largely remain unidentified because of the lack of a method for quantitative analysis of sialoglycoproteins. This manuscript presents a high throughput method for quantitative analysis of N-linked sialoglycoproteins using conditional hydrazide chemistry, liquid chromatography, and tandem mass spectrometry. We further applied the sialoglycoproteomic method to the profiling of breast cancer tissues and compared findings with the results from the total glycoproteomic analysis using the original hydrazide chemistry method. We identified altered expression of sialoglycoproteins, as well as the total glycoprotein changes associated with breast cancer. Using lectin and Western blot analysis, we characterized one of the sialoglycoproteins, versican, and confirmed that versican was most sialylated and elevated in breast cancer. Furthermore, we showed that versican was detected in both cancer epithelial cells and peritumoral stromal cells using immunohistochemistry. Tissue microarray analysis revealed that epithelial expression of versican had significant relations to lymph node metastasis and pathological stages. This is the first quantitative sialoglycoproteomic and glycoproteomic analysis of breast cancer and noncancerous tissues. These findings present a significant addition of the method to the identification of altered expression of sialylated glycoproteins associated with breast cancer development.

The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. Activation of the epithelial-to-mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal-to-epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow-derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research, outlines a unique paracrine cross-talk between the microenvironment and the cancer cells, which promotes tumor outgrowth in the metastatic organ, and discusses opportunities for novel antimetastatic approaches for cancer therapy.

BACKGROUND: Versican expression may enhance tumor invasion and metastasis. However, the expression of versican in human endometrial cancer has seldom been characterized. The aim of this study was to investigate versican expression in endometrial cancers. PATIENTS AND METHODS: We immunohistochemically investigated the expression of versican protein in 167 endometrial cancers and analyzed the correlation with various observed clinicopathological features, including patient outcome. RESULTS: Stromal versican expression was significantly higher in the advanced-stage (P = 0.010) and high-grade (P = 0.049) cancers, lymph node metastasis (P = 0.012), and ovarian metastasis (P = 0.024). Epithelial versican expression was significantly higher in patients with lymph node metastasis (P = 0.014) and lymph-vascular space involvement (P = 0.014). The disease-free survival (DFS) and overall survival (OS) rates of patients exhibiting high stromal versican expression were significantly lower than those of patients exhibiting low stromal versican expression (P < 0.0001). Multivariate analysis showed that high stromal versican expression was an independent prognostic factor for DFS and OS. CONCLUSIONS: Versican enrichment of the stroma may be associated with tumor progression in endometrial cancer. Stromal versican expression can serve as an indicator of poor prognosis for patients with endometrial cancer.

Although the main cause of gastrointestinal stromal tumor (GIST) is gain-of-function mutations in the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit appear to occur in the development of metastasis. We sought to identify the genes involved in the metastatic process of gastric GIST. Microarray analysis was performed to compare gene expressions between three gastric GIST and four metastatic liver GIST. expression levels were higher for 165 genes and lower for 146 genes in metastatic liver GIST. The upregulation of five oncogenes and downregulation of four tumor suppressor genes including versican and CD9 were confirmed by quantitative reverse transcriptional PCR. Immunohistochemistry in 117 GIST revealed that protein levels of versican and CD9 were higher and lower, respectively, in metastatic GIST. High expression of versican and low expression of CD9 in 104 primary gastric GIST correlated with poor disease-free survival (P = 0.0078 and P = 0.0018). In addition to the c-kit gene mutation, genetic or epigenetic changes other than c-kit play important roles in the metastatic process. In particular, versican and CD9 are potential prognostic markers in gastric GIST.

Forkhead box Q1 (FoxQ1) is a master regulator of tumor metastasis. However, the molecular mechanism of FoxQ1 in regulating hepatocellular carcinoma (HCC) metastasis remains unknown. Here we report a novel function for FoxQ1 in modifying the tumor microenvironment to promote HCC metastasis. FoxQ1 expression was an independent and significant risk factor for the recurrence and survival in two independent cohorts totaling 1,002 HCC patients. FoxQ1 induced epithelial-mesenchymal transition (EMT) through the transactivation of ZEB2 expression by directly binding to the ZEB2 promoter. Knockdown of ZEB2 decreased FoxQ1-enhanced HCC metastasis, whereas up-regulation of ZEB2 rescued the decreased metastasis induced by FoxQ1 knocking down. Additionally, serial deletion, site-directed mutagenesis, and a chromatin immunoprecipitation assays showed that VersicanV1, which promoted HCC metastasis and macrophage attraction, was a direct transcriptional target of FoxQ1. FoxQ1-induced VersicanV1 expression promoted the secretion of chemokine (C-C motif) ligand 2 (CCL2) from HCC cells. Chemotaxis assay showed that the culture media from FoxQ1-overexpressing HCC cells increased the migratory activity of the macrophages. Inhibition of VersicanV1 and CCL2 expression significantly inhibited FoxQ1-mediated macrophage migration. In animal studies, the up-regulation of FoxQ1 in HCC cells promoted HCC metastasis and intratumoral tumor associated macrophage (TAM) infiltration, whereas knockdown of VersicanV1 reduced FoxQ1-mediated HCC metastasis and intratumoral TAM infiltration. Depletion of macrophages using clodronate liposomes dramatically decreased FoxQ1-enhanced HCC metastasis. In human HCC tissues, FoxQ1 expression was positively correlated with ZEB2 and VersicanV1 expression and intratumoral TAM infiltration. Patients with positive coexpression of FoxQ1 and ZEB2, FoxQ1, and VersicanV1, or FoxQ1 and intratumoral TAMs were associated with poorer prognosis. CONCLUSION: FoxQ1 promotes HCC metastasis by transactivating ZEB2 and VersicanV1 expression, resulting in the induction of EMT and the recruitment of macrophage infiltration.

The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. Activation of the epithelial-to-mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal-to-epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow-derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research, outlines a unique paracrine cross-talk between the microenvironment and the cancer cells, which promotes tumor outgrowth in the metastatic organ, and discusses opportunities for novel antimetastatic approaches for cancer therapy.