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ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction Abdo J

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ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction Abdo J Research Article ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction Abdo J. Najy,1,2 Kathleen C. Day,1 and Mark L. Day1,2 1Department of Urology and 2Program in Cellular and Molecular Biology and University of Michigan, Ann Arbor, Michigan Abstract The less studied ADAM (a disintegrin and metalloproteinase) Using human tumor and cDNA microarray technology, we family of membrane metalloproteinases may also support tumor progression by modulating key physiologic cell surface proteins have recently shown that the ADAM15 disintegrin is signifi- such as membrane-anchored growth factors and their comple- cantly overexpressed during the metastatic progression of mentary receptors, cell adhesion molecules, and integrins (4). The human prostate cancer. In the current study, we used ADAM family is composed of 40 members, of which 13 members lentiviral-based short hairpin RNA (shRNA) technology to are catalytically active. These catalytically active members contain down-regulate ADAM15 in the metastatic prostate cancer cell a metalloproteinase domain that is implicated in growth factor line, PC-3. ADAM15 down-regulation dramatically attenuated shedding and extracellular matrix (ECM) degradation. ADAM17 many of the malignant characteristics of PC-3 cells in vitro has been reported to process pro–tumor necrosis factor (TNF)-a, and prevented the s.c. growth of PC-3 cells in severe combined TNF receptors, interleukin-6 receptor, and amphiregulin (5, 6), immunodeficient (SCID) mice. By inhibiting the expression of and ADAM9, ADAM10, ADAM12, and ADAM17 are believed to ADAM15 in PC-3 cells, we showed decreased cell migration cleave the epidermal growth factor receptor (EGFR) ligand, HB- and adhesion to specific extracellular matrix proteins. This EGF, leading to the transactivation of EGFR (7). ADAM family was accompanied by a reduction in the cleavage of N-cadherin members have also been shown to cleave different cell adhesion by ADAM15 at the cell surface. Fluorescence-activated cell molecules such as N-cadherin (8). Expression of N-cadherin in sorting analysis revealed reduced cell surface expression of the human tumor cells is usually associated with malignant progres- metastasis-associated proteins A integrin and CD44. Further- v sion (9). Cell surface N-cadherin supports heterotypic interaction more, matrix metalloproteinase 9 secretion and activity were between migrating cancer cells and other cells of the tumor abrogated in response to ADAM15 reduction. In an in vitro microenvironment such as fibroblasts and endothelial cells to model of vascular invasion, loss of ADAM15 reduced PC-3 support cancer cell migration, invasion, and metastasis. adhesion to, and migration through, vascular endothelial cell Another physiologic feature of ADAMs uses the disintegrin monolayers. Using an SCID mouse model of human prostate domain to mediate integrin-ECM interactions. Several ADAM cancer metastasis, we found that the loss of ADAM15 family members, including ADAM15, have been shown to bind to significantly attenuated the metastatic spread of PC-3 cells specific integrin molecules, suggesting roles in cellular adhesion to bone. Taken together, these data strongly support a and tumor cell-ECM interactions (10). Although the ADAMs have functional role for ADAM15 in prostate tumor cell interaction been the focus of rigorous research in many biological processes, with vascular endothelium and the metastatic progression of such as oocyte fertilization, neurogenesis, myogenesis, and growth human prostate cancer. [Cancer Res 2008;68(4):1092–9] factor shedding (11, 12), they have only recently been studied in the context of human tumorigenesis (13–15). For example, ADAM9 Introduction expression has been associated with the incident of low-grade The dissemination of localized prostate cancer to distant tissues prostate cancer formation in mice (16); however, the precise role of such as the bone, lung, and liver represents a prominent health care the ADAMs in malignant processes remains largely unknown. burden in the aging adult male population (1). The underlying A number of proteases, including members of the ADAM family, mechanisms that promote and support the metastatic spread of are thought to play regulatory roles in the processes of angio- prostate cancer remain vague. It is clear that fundamental genesis and neovascularization. ADAMs have been implicated in processes, such as cellular detachment, suppression of apoptosis, the processing of several key signaling components of inflamma- vascular intravasation, and angiogenesis are essential to the spread tion and angiogenesis as well as adhesion molecules that comprise of cancer cells and their growth at distant sites (2). One family of endothelial adherens junctions, including vascular endothelial proteins supporting malignant progression is the zinc-binding (VE)-cadherin, PCAM-1, and integrins (17). A novel role for matrix metalloproteinases (MMP) that degrade components of the ADAM15 in endothelial adhesion was suggested by the observation extracellular matrix, such as collagen, laminin, and fibronectin (3). that ADAM15 colocalized in endothelial cell junctions with VE- However, the MMPs are not the only metalloproteinases implicated cadherin (18). Additionally, Horiuchi and colleagues (19) provided a in human tumorigenesis. compelling argument for the role of ADAM15 in pathologic neovascularization using a model of prematurity of retinopathy in mice. Further supporting ADAM15 function in endothelial regulation is the evidence that ADAM15 binds the endothelial Note: Supplementary data for this article are available at Cancer Research Online a h a h (http://cancerres.aacrjournals.org/). integrins 5 1 and v 3 via an RGD motif contained within its Requests for reprints: Mark L. Day, Department of Urology, University of disintegrin domain (20, 21). Taken together, these studies suggest Michigan, 6219 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944. that ADAM15 is a potential but unexplored component of tumor Phone: 734-647-9968; Fax: 734-647-9271; E-mail: [email protected]. I2008 American Association for Cancer Research. cell–endothelial cell interaction that may play a role in tumor doi:10.1158/0008-5472.CAN-07-2432 angiogenesis and/or metastasis. Cancer Res 2008; 68: (4). February 15, 2008 1092 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. The Role of ADAM15 in Prostate Cancer Metastasis a Although a role for ADAM15 in tumor vasculature may be ADAM10, ADAM15, and v integrin (Chemicon); and ADAM17 and CD44 emerging, very little is known concerning the contribution of (R&D Systems). In vivo Luc ADAM15 to tumor initiation and progression. Located on tumorigenesis assay. PC3 cells were trypsinized, washed chromosome 1q21, the gene encoding ADAM15 maps to a region twice with PBS, collected, and resuspended in PBS; the viability of collected cells was tested by staining with trypan blue. To establish PC3Luc tumor of documented amplification associated with the metastatic xenografts in mice, 6-week-old C57BL/6 severe combined immunodeficient progression of human cancers, including prostate, breast, ovarian, (SCID) mice were injected s.c. in the right flank with 1 Â 107 vector or colon, and melanoma (22–24). We have recently completed the first shADAM15 PC3Luc cells in 100 AL of PBS. Tumor volume was monitored comprehensive expression profile of ADAM15 in human prostate weekly by external measurements with a caliper and calculated as cancer by using both cDNA microarray and multitumor array V =(L2 Â l) / 2, where L and l represent the smaller and the larger technology. This study showed significant increases of ADAM15 tumor diameter. The observations were ended for ethical reasons after expression in multiple adenocarcinomas and a highly significant 8 weeks due to large tumor burden in vector control mice. Animals were correlation with the metastatic progression of human prostate maintained under specific pathogen-free conditions with ad libitum food cancer (25). Based on previous work characterizing the catalytic and water in the University of Michigan animal housing facilities. At this metalloproteinase and disintegrin domains of ADAM15, we time, animals were euthanized by CO2 inhalation followed by induction of a bilateral pneumothorax and tumors were immediately frozen in dry ice or anticipated that ADAM15 may serve multiple functions in the fixed in formalin. metastatic progression of prostate tumors through disruption or In vitro migration assay. Cell migration was evaluated by using the degradation of the extracellular matrix, via its disintegrin domain, scratch wound assay; vector or shADAM15 PC-3Luc cells were cultured for as well as proteolytic processing of key membrane-bound 2 to 3 days to form a tight cell monolayer. Cells were then serum starved for molecules via the metalloproteinase domain. 16 h. Following the serum starvation, the cell monolayer was wounded with To specifically elucidate the role of ADAM15 in prostate cancer a10AL plastic pipette tip. The remaining cells were washed twice with progression, we developed a stable short hairpin RNA (shRNA)– culture medium to remove cell debris and incubated at 37jC with normal mediated knockdown of ADAM15 in the highly malignant prostate serum-containing culture medium. At the indicated times, migrating cells at cancer line PC-3. We have established that the reduction of the wound front were
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