title: Role of interleukin 10 and transforming growth factor beta1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice.
abstract: Transfection of primary human prostate tumor cells (i.e., HPCA-10a, 10b, 10c, and 10d lines) with the transforming growth factor (TGF)-beta1 gene stimulated anchorage-independent growth and promoted tumor growth, angiogenesis, and metastasis after orthotopic implantation in severe combined immunodeficiency mice. In contrast, interleukin (IL)-10 transfected cells or cells cotransfected with these two genes exhibited reduced growth rates and significantly reduced angiogenesis and metastasis after 8, 12, and 16 weeks. Enzyme-linked immunosandwich assays confirmed that the respective tumors expressed elevated levels of TGF-beta1 and IL-10 in vivo. ELISAs further showed that TGF-beta1 expression induced matrix metalloproteinases-2 (MMP-2) expression, whereas IL-10 down-regulated MMP-2 expression while up regulating TIMP-1 in the transfected cells. Also, tumor factor VIII levels correlated with TGF-beta1 and MMP-2 expression and inversely with IL-10 and TIMP-1 levels. More importantly, mouse survival was zero after 4-6 months in mice bearing TGF-beta1- and MMP-2-expressing tumors and increased significantly in mice implanted with IL-10- and TIMP-1-expressing tumors (i.e., to >80% survival). Analysis of the metastatic lesions showed that they expressed TGF-beta1 and MMP-2 but barely detectable levels of IL-10 or TIMP-1, suggesting that IL-10 and TIMP-1 might normally block tumor growth, angiogenesis, and metastasis.
authors: Medical College of Pennsylvania and Hahnemann University, Department of Pathology and Laboratory Medicine, Philadelphia 19102-1192, USA.
authors: M E
authors: ME
authors: Stearns
authors: F U
authors: FU
authors: Garcia
authors: K
authors: K
authors: Fudge
authors: J
authors: J
authors: Rhim
authors: M
authors: M
authors: Wang
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D018093:Gelatinases / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2