Modulation of the microenvironment and adhesion of cancer cells by ADAMs (a disintegrin and metalloproteinase).

Morphogenesis of malignant tumors is characterized by proliferation, invasive growth and metastasis. Although these properties are determined mainly by genetic derangements, their biological behavior within tissues is strictly regulated by tumor microenvironment, which consists of extracellular matrix, proteinases, soluble factors (cytokines/growth factors/chemokines), stromal cells and blood vessels. Thus, modulation of the microenvironment is implicated in morphogenesis in tumorigenesis. ADAMs (a disintegrin and metalloproteinases) are a new gene family of membrane-anchored and secreted proteins that have proteolytic and/or adhesive properties. They are involved in biological events including cell adhesion, cell fusion, membrane protein shedding and proteolysis. We examined the expression of the proteinase-type ADAMs in the invasive breast and lung carcinoma tissues, and found that membrane-anchored ADAM28m and secreted ADAM28s are selectively overexpressed in activated forms by carcinoma cells. The mRNA expression levels directly correlated with the proliferative activity of the carcinoma cells in both carcinomas, and with lymph node metastasis in the lung carcinomas. Our experimental studies showed that ADAM28 plays a key role in cancer cell proliferation through enhancing bioavailability of insulin-like growth factor-I (IGF-I) released from the IGF-I/IGF-binding protein 3 (IGFBP-3) complex by selective cleavage of IGFBP-3. We also identified P-selectin glycoprotein ligand-1 (PSGL-1) as a binding protein to ADAM28 by yeast two-hybrid system, and demonstrated that ADAM28s promotes PSGL-1/P-selectin-mediated HL-60 cell rolling adhesion to endothelial cells and subsequent transendothelial migration into tissue spaces. Altogether, our data suggest the possibility that ADAM28 expressed by cancer cells is involved in cancer cell proliferation and metastases in human cancers through modulation of tumor microenvironment and cell adhesion.