A Secreted Form of ADAM9 Promotes Carcinoma Invasion through Tumor-Stromal Interactions

Abstract

Tumor cell invasion is a process regulated by integrins, matrix-degrading enzymes, and interactions with host tissue stromal cells. The ADAM family of proteins plays an important role in modulating various cellular responses. Here, we show that an alternatively spliced variant of ADAM9 is secreted by hepatic stellate cells and promotes carcinoma invasion. ADAM9-S induced a highly invasive phenotype in several human tumor cell lines in Matrigel assays, and the protease activity of ADAM9-S was required for invasion. ADAM9-S binds directly to A 6 B 4 and A 2 B 1 integrins on the surface of colon carcinoma cells through the disintegrin domain. ADAM9-S was also able to cleave laminin and promote invasion. Analysis of human liver metastases revealed that ADAM9 is expressed by stromal liver myofibroblasts, particularly those that are localized within the tumor stroma at the invasive front. These results emphasize the importance of tumor-stromal interactions in invasion and suggest that ADAM9-S can be an important determinant in the ability of cancer cells to invade and colonize the liver. (Cancer Res 2005; 65(11): 4728-38)

Stromal myofibroblasts are drivers of invasive cancer growth

“…So, epithelial mesenchymal transition is ''classical'' for renal fibrosis, and typical resident stellate cells transdifferentiate to myofibroblasts in liver and pancreatic fibrosis. 29,30 In lung fibrosis, epithelial and endothelial transitions are frequent events, but in vitreo-retinopathies the myofibroblasts are recruited into the epiretinal membranes from circulating fibrocytes 43 (see Fig. 2).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…As a matter of fact, several ADAMs have been associated with cancer development and progression; for example ADAM12 is upregulated in hematologic, breast and gastric malignancies Lendeckel et al, 2005;Wu et al, 1997) and ADAM10 is highly expressed in pheochromocytoma and neuroblastoma (Yavari et al, 1998). ADAMs involvement in tumor biology can be explained by different mechanisms, since (i) ADAMs (i.e., ADAM9) could cleave ECM components, such as laminin, and promote cell invasion, similarly to MMPs; (ii) the shedding of adhesion molecules could affect cell adhesion to vasculature; (iii) the shedding of growth factors and their receptors may alter cell growth, as documented for ADAM17 and TNF-a in breast cancer (Kenny and Bissell, 2007;Mazzocca et al, 2005;Tousseyn et al, 2006). The shedding of adhesion molecules directly links ADAMs with inflammatory response, being involved in leukocyte recruitment (Garton et al, 2006;Hafezi-Moghadam and Ley, 1999;Schulz et al, 2008).…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Hence, ADAM-12 might contribute to growth inhibitory signalling in normal epithelial cells which is lost during tumour progression. ADAM-9 promotes invasiveness of liver metastatic carcinoma cells by degrading basement membrane components such as laminin-1 [141]. ADAM-9 is differentially expressed in stromal or epithelial cells and a soluble variant of ADAM-9 is secreted by activated hepatic stellate cells but not carcinoma cells or hepatocytes, indicating that stroma production of ADAM-9 might be of particular importance.…”

“…ADAM-9 is overexpressed in a colon cell line and is co-localized with Ecadherin suggesting a potential role in E-Cadherin-mediated metastasis [141,155]. ADAMTS-1 has recently been recognized as a novel gene inactivated through promoter hypermethylation in colorectal tumour development [156].…”