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Promotion of Angiogenesis by Ps20 in the Differential Reactive Stroma Prostate Cancer Xenograft Model1

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Promotion of Angiogenesis by Ps20 in the Differential Reactive Stroma Prostate Cancer Xenograft Model1 [CANCER RESEARCH 63, 5859–5865, September 15, 2003] Promotion of Angiogenesis by ps20 in the Differential Reactive Stroma Prostate Cancer Xenograft Model1 Stephanie J. McAlhany, Steven J. Ressler, Melinda Larsen,2 Jennifer A. Tuxhorn,3 Feng Yang, Truong D. Dang, and David R. Rowley4 Department of Molecular and Cellular Biology [S. J. M., S. J. R., J. A. T., F. Y., T. D. D., D. R. R.] and Cell and Molecular Biology Program [M. L.], Baylor College of Medicine, Houston, Texas 77030 ABSTRACT gresses with the developing cancer foci (1). This reactive stroma is composed primarily of the myofibroblast cell type, and exhibits ECM5 Human prostate cancer is associated with a reactive stroma typified by remodeling and gene expression similar to a wound repair type stroma an increase in the proportion of myofibroblast type cells and elevated (1). The DRS xenograft model was developed to examine the effects synthesis of extracellular matrix proteins. Increased vascular density has been identified in the reactive stroma compartment adjacent to both of different prostate stromal cells and stromal gene expression on precancerous and cancerous prostate lesions. The differential reactive progression of LNCaP human prostate cancer cell xenografts in nude stroma (DRS) prostate cancer xenograft model has been developed to mice. These studies have shown that reactive stroma is tumor pro- investigate the role of reactive stroma in prostate cancer progression. moting and that a key early biological action of reactive stroma is the Using this model, we have shown that human prostate stromal cells promotion of angiogenesis (2). Tumors generated in the absence of promote angiogenesis and growth of LNCaP human prostate carcinoma human prostate stroma were significantly delayed in establishing new cell tumors, and that these increases are transforming growth factor blood vessels, resulting in more heterogeneous tumors with ill-defined ␤ (TGF) 1 regulated. Our laboratory isolated and identified previously the vascularity and the appearance of blood lakes in lieu of vessels. In ps20 protein (WFDC1 gene) as a prostate stromal cell secreted protein. The ps20 protein contains a whey acidic protein-type four-disulfide core contrast, DRS tumors constructed with some, but not all, of the human domain, which is a functional motif characterized by serine protease prostate stromal cell lines exhibited angiogenesis as early as day 4 inhibition activity in a number of whey acidic protein domain-containing with extensive vascularity by day 10, illustrating the differential proteins. In the present study, we show ps20 expression by normal human biology of human prostate stroma. In similar DRS tumors, ␤-galac- prostate stromal smooth muscle cells and vascular smooth muscle cells tosidase expressing stromal cells assumed a pericyte position in newly indicating a possible role of ps20 in vessel wall biology. Using in vitro formed capillaries, suggesting a direct interaction with developing assays, we show that ps20 promotes endothelial cell motility but has no vessels (2). In addition, we have reported that the promotion of effect on endothelial cell proliferation. To address the potential effects of angiogenesis in DRS tumors by stroma was TGF-␤1 regulated (3). ps20 in a tumor microenvironment, we used the DRS model to evaluate These studies have directed our interest to factors that specifically both angiogenesis and tumorigenesis of tumors generated under either ps20 or control conditions. DRS tumors generated with LNCaP and regulate new vessel formation and maintenance. human prostate stromal cells in the presence of ps20 showed a 67% Our previous studies have reported that the ps20 protein is ex- increase in microvessel density compared with control tumors. Elevated pressed by prostate stromal cells with strong expression in vessel wall DRS tumor growth in the ps20-treated tumors was reflected by a 29% smooth muscle cells (4). Originally, we characterized ps20 as a increase in wet weight and a 58% increase in volume compared with growth inhibitor of epithelial cells in vitro and purified ps20 to controls. Similar tumors composed of GeneSwitch-3T3 cells engineered to homogeneity from the conditioned medium of a fetal rat urogenital express ps20-V5-His under mifepristone regulation showed a 129% in- sinus mesenchymal cell line (5, 6). Subsequently, we cloned and crease in microvessel density after induction of ps20-V5-His. GeneSwitch- characterized the cDNA encoding rat ps20 (4), human ps20 cDNA, 3T3 cells expressing ps20-V5-His were localized to vessel walls in a mural and genomic DNA encoding the gene we termed WFDC1, as well as cell (pericyte) position indicating a possible direct stabilizing interaction with endothelial cells. In addition, we show that ps20 mRNA synthesis is genomic clones containing mouse ps20 (Wfdc1; Ref. 7). These studies induced by TGF-␤1, a known regulator of endothelial cell-pericyte inter- also localized WFDC1 to human chromosome 16q24 (7). In addition, actions and of stromal cell-induced angiogenesis in DRS tumors. These Rodriguez-Rey et al. recently cloned and submitted a chicken ps20 findings suggest that ps20 may be a TGF-␤1-induced regulator of angio- cDNA to the GenBank/European Molecular Biology Laboratory da- genesis that functions by either promoting endothelial cell migration or by tabase (AJ438920). There is high conservation of ps20 between spe- contributing to pericyte stabilization of newly formed vascular structures. cies, ranging from 61% to 96% identity of the mature protein. Each ps20 protein sequence contains a functional motif identified INTRODUCTION as a WAP type-four disulfide core domain consisting of eight cys- teines forming four characteristically paired disulfide bonds. The Prostate cancer is typified by the coevolution of a reactive stroma, domain and protein family is named after the first characterized which initiates during prostatic intraepithelial neoplasia and pro- member, WAP (8). The WAP domain confers a serine protease inhibition activity to several family members including elafin and Received 4/24/03; revised 6/25/03; accepted 6/30/03. SLPI (9, 10). Elafin is a potent inhibitor of elastase and proteinase 3, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with each of which are elastin-degrading proteases (11). SLPI inhibits a 18 U.S.C. Section 1734 solely to indicate this fact. broader range of serine proteases including trypsin, chymotrypsin, 1 Supported by NIH Grants RO1-CA58093, RO1-DK45909, Specialized Programs of elastase, and cathepsin G (11). Both elafin and SLPI are secreted Research Excellence CA58204, and UO1-CA84296. S. J. M. is a Hudson Scholar of the Baylor College of Medicine Medical Scientist Training Program. proteins known to protect host tissues from the effects of excessive 2 Present address: Craniofacial Developmental Biology and Regeneration Branch, proteolysis and to promote appropriate tissue repair in numerous National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, MSC 4370, Bethesda, MD 20892-4370. 3 Present address: Wyle Laboratories, Life Sciences Systems and Services, 1290 5 The abbreviations used are: ECM, extracellular matrix; DRS, differential reactive Hercules Drive, Houston, TX 77058. stroma; BAE, bovine aortic endothelial; HUVEC, human umbilical vein endothelial cell; 4 To whom requests for reprints should be addressed, at Department of Molecular and ps20, prostate stromal 20 kDa; SLPI, secretory leukocyte protease inhibitor; sm ␣-actin, Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798- smooth muscle ␣-actin; TGF, transforming growth factor; WFDC1, whey acidic protein- 6220; Fax: (713) 790-1275; E-mail: [email protected]. type four-disulfide core-1; WAP, whey acidic protein; CHO, Chinese hamster ovary. 5859 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2003 American Association for Cancer Research. ps20 PROMOTES ANGIOGENESIS model systems (12–14). These data suggest a role for these protease calf serum, 100 units/ml penicillin, 100 ␮g/ml streptomycin, and 0.29 mg/ml inhibitors in reactive stroma biology at numerous tissue sites. On the L-glutamine (Invitrogen). Cultures between passages 10 and 20 were used for basis of the immunolocalization of ps20 to smooth muscle cells and these studies. the presence of a signal peptide with secretion of the native protein HUVECs (Clonetics, Walkersville, IL) were cultured in endothelial cell from cells in vitro, it is theorized that ps20 is secreted by smooth growth medium-2 (Clonetics). Cells between passages 3 and 8 were used in muscle cells in vivo and is a component of the ECM environment, these studies. where it may function as a serine protease inhibitor. LNCaP human prostate carcinoma cells (American Type Culture Collec- The purpose of the present study was to additionally evaluate ps20 tion) were cultured in RPMI 1640 (Invitrogen) supplemented with 10% fetal ␮ expression in human prostate stroma, including vessels, and to deter- bovine serum, 100 units/ml penicillin, and 100 g/ml streptomycin. mine the effects of ps20 on endothelial cell migration, angiogenesis, HPS-19B human prostate stromal cells were established using our protocols reported previously (6, 17). Briefly, prostate tissue from a 19-year-old organ and tumorigenesis using in vitro assays, and the DRS xenograft donor was obtained from the Baylor College of Medicine
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