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.