Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M et al.. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 65: 4728-4738

University of Florence, Florens, Tuscany, Italy
Cancer Research (Impact Factor: 9.33). 07/2005; 65(11):4728-38. DOI: 10.1158/0008-5472.CAN-04-4449
Source: PubMed


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 alpha6beta4 and alpha2beta1 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.

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    • "Invasion was performed as previously described [15]. Briefly, 8 μm trans-well membranes (Corning Life Sciences, Manassas, VA, USA) were pre-coated with 20 μg/ml BD Matrigel™ Basement Membrane Matrix (BD Biosciences, Buccinasco (MI), Italy). "
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    ABSTRACT: Thrombocytopenia has been reported to be associated with small size HCCs, and thrombocytosis to be associated with large size HCCs. The aim was to examine the effects of platelets in relation to HCC cell growth. The effects of time-expired pooled normal human platelets were examined on human HCC cell line growth and invasion. Blood platelet numbers increased with increasing HCC tumor size and portal vein invasion. Platelet extracts enhanced cell growth in 4 human HCC cell lines, as well as cell migration, medium AFP levels and decreased apoptosis. Cell invasion was significantly enhanced, using a Matrigel-coated trans-well membrane and3D (Real-Time Imaging)invasion assay. Western blots showed that platelets caused enhanced phospho-ERK and phospho-JNK signaling and anti-apoptotic effect with increase of Bcl-xL (anti-apoptotic marker) and decrease of Bid (pro-apoptotic marker) levels. Their growth effects were blocked by a JNK inhibitor. Platelets stimulated growth and invasion of several HCC cell lines in vitro, suggesting that platelets or platelet growth factors could be a potential pharmacological target.
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    • "Although ADAM9 is normally considered a transmembrane protein, a soluble form ADAM9-S has been described [30], which is derived from alternative splicing of the gene [31]. The ADAM9-S protein promotes the invasive phenotype of carcinoma cell lines, and ADAM9 is strongly expressed at the invading front of hepatic metastases, although the authors did not distinguish ADAM9 and ADAM9-S [31]. Taken together, these studies suggest that ADAM9 has a significant role in tumorigenesis and metastasis. "
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    ABSTRACT: ADAM9 (A Disintegrin And Metalloproteinase 9) is a member of the ADAM protein family which contains a disintegrin domain. This protein family plays key roles in many physiological processes, including fertilization, migration, and cell survival. The ADAM proteins have also been implicated in various diseases, including cancer. Specifically, ADAM9 has been suggested to be involved in metastasis. To address this question, we generated ADAM9 knockdown clones of MDA-MB-231 breast tumor cells using silencing RNAs that were tested for cell adhesion, proliferation, migration and invasion assays. In RNAi-mediated ADAM9 silenced MDA-MB-231 cells, the expression of ADAM9 was lower from the third to the sixth day after silencing and inhibited tumor cell invasion in matrigel by approximately 72% when compared to control cells, without affecting cell adhesion, proliferation or migration. In conclusion, the generation of MDA-MB-231 knockdown clones lacking ADAM9 expression inhibited tumor cell invasion in vitro, suggesting that ADAM9 is an important molecule in the processes of invasion and metastasis.
    Full-text · Article · Mar 2013 · Biochimie
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    • "The DIS domain of ADAM9 may directly bind to α6β4 and α2β1 integrins and proteolytic activity of this adamalysin allows to cleave laminines. The in vitro studies on CRC cell lines reveled the influence of ADAM9s overexpression on increased invasiveness of cancer cells (98). The investigation on CRC HT29 cell line pointed out the influence of overexpression of ADAM9 transmembrane forms on the HB-EGF-induced increased proliferation and decreased cell adhesion via E-cadherin degradation. "
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    ABSTRACT: The ADAM and ADAMTS families, also called adamalysins belong to an important group of extracellular matrix proteins. The ADAMs family belong to both the transmembrane and secreted proteins, while ADAMTS family only contains secreted forms. Adamalysins play an important role in the cell phenotype regulation via their activities in signaling pathways, cell adhesion and migration. The human proteome contains 21 ADAM, and 19 ADAMTS proteins, which are involved in extracellular matrix remodeling, shedding of various substrates such as: adhesion ligands, growth factors, their receptors and diverse cytokines. Recent studies provide evidence that adamalysins play a crucial role in colorectal cancer (CRC) etiopathogenesis. It seems possible that adamalysins might be used as CRC prediction markers or potential pharmaceutical targets. [BMB Reports 2013; 46(3): 139-150].
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