Abstract
ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in patients with advanced disease.
Highlights
Bladder cancer is the fourth most common cause of cancer, and the eighth most common cause of cancer death in men
By further analyzing 3 independent transcriptome studies in OncomineTM (Sanchez, Lee and Blaveri), we found significant overexpression of ADAM15 mRNA in infiltrating bladder cancer compared to normal tissues (Fig 1B)
ADAM15 is a multi-domain disintegrin metalloproteinase that is upregulated in several solid malignancies including prostate and breast cancer and elevated expression of ADAM15 has been correlated with the metastatic progression of these tumors [19,20,21]
Summary
Bladder cancer is the fourth most common cause of cancer, and the eighth most common cause of cancer death in men. An estimated 74,000 men and women will be diagnosed and 16,000 people will die of bladder cancer by the end of 2015 [1]. While the majority of bladder cancers present as noninvasive early stage tumors, up to one third of non-muscle invasive disease will progress to muscle invasive disease and metastasize over time [2]. Most bladder cancers express elevated levels of the epidermal growth factor receptor (EGFR) [5,6,7]. Elevated EGFR is common in primary bladder cancers with about 50% of cases exhibiting overexpression [8]. A majority of metastatic bladder tumors have been shown to express EGFR [11]. Biological pathways that enhance growth factor signaling through EGFR are likely to contribute to bladder cancer progression and metastasis. Cellbound EGFR ligands, such as heparin-binding epidermal growth factor (HB-EGF), amphiregulin, transforming growth factor alpha (TGFα), and betacellulin are known to be released through the action of membrane-bound proteases including members of the ADAM (A Disintegrin And Metalloproteinase) family [12,13,14]
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