ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Abstract

ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our aim was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue inhibitor of metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.

ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer

“…It belongs to a matrix metalloproteinase-related protein family and participates in the proteolytic processing of other transmembrane proteins, with consequences for cell-signalling events, transcription, RNA metabolism, apoptosis, cell-cycle progression, and cell adhesion. ADAM12 overexpression has been reported in many tumours [31,32], especially in BC, where it has been proposed to make an important contribution in carcinogenesis [33][34][35][36]. However, its molecular status in the TNBC subtype is almost entirely unexplored.…”

Metalloproteinases and their roles in human cancer

“…Extensive studies have demonstrated the importance of MMPs and ADAMs in the regulation of angiogenesis (Moses et al, ; Harper and Moses, ; Sun et al, ). Tumor cells as well as endothelial and other stromal cells in the tumor microenvironment express and release these proteases which, upon activation, can degrade the ECM components around the vasculature leading to the facilitation of vessel sprouting (Song et al, ; Roy et al, ). MMP‐derived modulation of ECM and receptors can also promote angiogenesis through activating different pro‐angiogenic signaling pathways (Fig.…”

“…Our group has demonstrated that ADAMs also contribute to angiogenesis through activation of signaling pathways. Tumor expression of ADAM12 leads to the activation of EGFR/STAT3 signaling pathway resulting in an increase in the expression of pro‐angiogenic factors and decrease in the expression of antiangiogenic factors (Roy et al, ). Degradation of angiostatic factors is another mechanism with which MMPs promote angiogenesis.…”

Nanomaterial Preparation by Extrusion through Nanoporous Membranes

“…In the rapidly developing field of disease diagnosis research, many native disease biomarkers (e.g., urine and blood proteins, circulating tumor DNAs and others) exist at very low concentrations (e.g., nanomolar or lower) with short half-life times (e.g., minutes or shorter). [208][209][210][211][212][213][214][215] One possible way to detect these biomolecules at ultralow concentration is to capture these biomolecules using micro-/ nanoparticles at single molecular levels and then amplify the detection signals based on the unit of micro-/nanoparticles. One prominent example was reported by Rissin et al who utilized magnetic microparticles to capture and detect serum proteins at a concentration as low as 14 fg mL −1 .…”