Genetic Inactivation of ADAMTS15 Metalloprotease in Human Colorectal Cancer

Abstract

Matrix metalloproteinases have been traditionally linked to cancer dissemination through their ability to degrade most extracellular matrix components, thus facilitating invasion and metastasis of tumor cells. However, recent functional studies have revealed that some metalloproteases, including several members of the ADAMTS family, also exhibit tumor suppressor properties. In particular, ADAMTS1, ADAMTS9, and ADAMTS18 have been found to be epigenetically silenced in malignant tumors of different sources, suggesting that they may function as tumor suppressor genes. Herein, we show that ADAMTS15 is genetically inactivated in colon cancer. We have performed a mutational analysis of the ADAMTS15 gene in human colorectal carcinomas, with the finding of four mutations in 50 primary tumors and 6 colorectal cancer cell lines. Moreover, functional in vitro and in vivo studies using HCT-116 and SW-620 colorectal cancer cells and severe combined immunodeficient mice have revealed that ADAMTS15 restrains tumor growth and invasion. Furthermore, the presence of ADAMTS15 in human colorectal cancer samples showed a negative correlation with the histopathologic differentiation grade of the corresponding tumors. Collectively, these results provide evidence that extracellular proteases, including ADAMTS15, may be targets of inactivating mutations in human cancer and further validate the concept that secreted metalloproteases may show tumor suppressor properties. [Cancer Res 2009;69(11):4926-34]

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

“…As apoptotic property has not been reported for ADAMTS members, this study indicates the possibility that other ADAMTS members may also involve in the regulation of apoptosis. We further found that the inhibition of tumor cell growth and induction of apoptosis by ADAMTS8 are associated with deregulation of EGFR-MEK-ERK signaling pathway, and secreted ADAMTS8 also exhibits inhibitory effect on EGFR signaling, in line with the findings in ADAMTS1 and ADAMTS15, another 2 members of the same subgroup (4,33). Thus, we report here that ADAMTS8 is another ADAMTS member displaying antitumorigenic (4,33,34).…”

“…However, this concept is challenged by recent findings of several members showing to possess tumor suppressive functions (2)(3)(4)(5)(6). A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS), a family of extracellular metalloproteases, is structurally and functionally similar to matrix metalloproteinases (MMP) and ADAMs (7).…”

New Negative Feedback Regulators of Egfr Signaling inDrosophila

“…Evidence, however, is emerging that ADAMTS proteins can also function as tumor suppressors. ADAMTS1, ADAMTS12, and ADAMTS15 act as tumor suppressors in prostate, colon, and breast cancer (Porter et al 2006;Moncada-Pazos et al 2009;Viloria et al 2009;El Hour et al 2010;Molokwu et al 2010). Our genetic evidence shows CG4096 has an inhibitory effect on Egfr activity.…”

Expression Profiles and Clinical Correlations of Degradome Components in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma

“…Despite this, there is growing recognition that several ADAMTS family members are tumor suppressors (9). This is the case for ADAMTS15 whose elevated expression correlates with favorable outcome in patients with breast cancer (45) and which acts as a functional tumor suppressor in colorectal cancer (46). Recently, of great relevance, ADAMTS9 is deleted or silenced by methylation in esophageal SCC (47).…”