7412

VCAM1

vascular cell adhesion molecule 1;VCAM1;vascular cell adhesion molecule 1

CD106 antigen|vascular cell adhesion protein 1

1p32-p31

protein-coding

Endothelial cell adhesion molecules (CAMs) are important in tumorigenesis and host defense mechanism. Their status in breast cancer with regard to nodal invasion is not yet known. Hence we looked at the expression of three important CAMs: VCAM, ICAM and E-selectin. A downregulation of all these CAMs was noted in node positive breast cancer in comparison to node negative cases. This suggests shedding of these molecules in cases with nodal metastasis which might help the tumor cells to escape the host defense mechanism. On multi-variate analysis, VCAM alone emerged as an independent predictor of nodal metastasis.

Interactions between disseminated tumor cells (DTC) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates prometastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in 2 different organs--lung and bone--is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counterreceptor, the alpha4beta1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1-mediated activation of the phosphoinositide 3-kinase growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers alpha4 integrin-expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the alpha4 integrin-VCAM-1 interactions in metastatic breast cancer. Anti-alpha4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained U.S. Food and Drug Administration approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer.

Colorectal cancer (CRC) is one of the most common cancers of the gastrointestinal tract and the fourth cause of cancers death in the world. Soluble adhesion molecules (CAMs) are thought to have an important role in host defense against carcinogenesis. They are biomarkers of inflammation and indicators of the immune response to tumors. The study included 40 CRC patients without remote metastases and 24 control subjects. Serum concentrations of sE-selectin, sICAM and sVCAM in patients with CRC were investigated by ELISA method. The level of the sCAMs decreased significantly after radical tumor resection. Preoperative serum concentrations of sICAM and sVCAM in CRC patients were significantly higher compared to the control group, whereas there were no differences regarding serum sE-selectin. Serum levels of sE-selectin, sICAM and sVCAM correlated significantly with each other. There was a significant correlation of serum levels of sICAM-1 and sVCAM-1, but not sE-selectin, with TNM stage and lymph node involvement. No significant relationship was found between serum concentrations of sICAM-1, sVCAM-1 and sE-selectin in CRC patients and patients' age or gender. Our findings suggest that an improved understanding of the mechanisms of membrane shedding of sICAM, sVCAM and sE-selectin is required to delineate their role in tumor progression.

BACKGROUND/AIMS: Cell adhesion molecules play a critical role in the invasion and metastasis of a variety of human tumors. Abnormal expression of VCAM-1 has been demonstrated to correlate with the malignant progression of gastric tumors, but the molecular mechanism underlying the VCAM-1-dependent metastasis has been rarely investigated. To explore the role for tumor cell-expressing adhesion molecules in the carcinoma-endothelium adhesion, we analyzed expression status of adhesion molecules in gastric cancer cells and its association with tumor cell capability of endothelial adhesion. METHODS: Endothelial adhesion ability of gastric tumor cells was tested using calcein AM staining assay. expression of cell surface proteins was determined by Western blot, flow cytometry, and immunofluorescence assays. RNAi-mediated knockdown of gene expression and neutralization with specific antibodies were utilized for functional analysis. RESULTS: One of three cell lines tested was identified to be adhesive to endothelial cells and express VCAM-1. Adherence ability of the cells was dramatically decreased by neutralization of surface VCAM-1. VCAM-1 was co-localized with Caveolin-1 and siRNA-mediated knockdown of Caveolin-1 expression significantly blocked the VCAM-1-dependent cell adhesion. CONCLUSIONS: Our data imply important roles for VCAM-1 and Caveolin- 1 in the regulation of metastatic potential of gastric tumor cells.

OBJECTIVE: To investigate the expression and significance of vascular cell adhesion molecule-1 (VCAM-1) and P-selectin in hypopharyngeal carcinoma, and explore the relationship of VCAM-1, P-selectin and microvessel density (MVD). METHOD: expression of VCAM-1 and P-selectin were detected by immunohistochemistry staining in 40 specimens of hypopharyngeal carcinoma and 10 specimens of normal mucosa of oral pharynx. MVD was assessed based on the expression of CD34. RESULT: VCAM-1 and P-selectin were detected in 26 out of 40 (65%) and 29 out of 40 (72.5%) respectively in hypopharyngeal carcinoma, but none that in normal mucosa (P<0.01). MVD in hypopharyngeal carcinoma was higher than that in normal mucosa and it was related to lymph node metastasis. MVD level was significantly higher in VCAM-1 and P-selectin-positive specimens than in negative ones (P<0.01), which also positively correlated with the expression of VCAM-1 and P-selectin (P<0.01). The expression of P-selectin positively correlated with VCAM-1 in hypopharyngeal carcinoma specimens with lymph node metastasis. CONCLUSION: The higher expression of VCAM-1 and P-selectin play key roles in the invasion and metastasis of hypopharyngeal carcinoma and were correlated with vascularization.

The capacity of tumor cells to form metastatic foci correlates with their ability to interact with and migrate through endothelial cell layers. This process involves multiple adhesive interactions between tumor cells and the endothelium. Only little is known about the molecular nature of these interactions during extravasation of tumor cells. In human melanoma cells, the integrin alphavbeta3 is involved in transendothelial migration and its expression correlates with metastasis. However, many human melanoma cells do not express beta3 integrins. Therefore, it remained unclear how these cells undergo transendothelial migration. In this study we show that human melanoma cells with different metastatic potency, which do not express beta2 or beta3 integrins, express the VCAM-1 receptor alpha4beta1. VCAM-1 is up-regulated on activated endothelial cells and is known to promote transendothelial migration of leukocytes. Interestingly, despite comparable cell surface levels of alpha4beta1, only the highly metastatic melanoma cell lines MV3 and BLM, but not the low metastatic cell lines IF6 and 530, bind VCAM-1 with high affinity without further stimulation, and are therefore able to adhere to and migrate on isolated VCAM-1. Moreover, we demonstrate that function-blocking antibodies against the integrin alpha4beta1, as well as siRNA-mediated knock-down of the alpha4 subunit in these highly metastatic human melanoma cells reduce their transendothelial migration. These data imply that only high affinity interactions between the integrin alpha4beta1 on melanoma cells and VCAM-1 on activated endothelial cells may enhance the metastatic capacity of human beta2/beta3-negative melanoma cells.

Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5-year survival <25%). Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface receptor that mediates leukocyte attachment and extravasation across endothelial and mesothelial monolayers at sites of inflammation. Membranous VCAM-1 expression was observed on the mesothelium of 13 of 14 women with ovarian cancer compared with 6 of 15 who were cancer-free. Using a cell culture model system of mesothelial invasion, highly tumorigenic SKOV-3 and ES-2 cells were 2.5 to 3 times more efficient in transmigration through the mesothelial monolayer compared with poorly tumorigenic OVCAR-3 cells. Blocking antibodies to, or small interfering RNA knockdown of, VCAM-1 or its ligand alpha(4)beta(1) integrin significantly decreased, but did not completely inhibit, transmigration of SKOV-3 cells through mesothelial monolayers. Furthermore, using a mouse model of ovarian cancer metastasis, treatment with VCAM-1 function-blocking antibodies decreased tumor burden and increased survival. Together, these observations implicate VCAM-1-alpha(4)beta(1) integrin interactions in the regulation of ovarian cancer cell mesothelial invasion and metastatic progression and offer the possibility of novel therapeutic targets.