Role of interleukin 10 and transforming growth factor beta 1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopicimplants in severe combined immunodeficiency mice

Transfection of primary human prostate tumor cells (i.e., HPCA-10a, 10b, 10 c, and 10d lines) with the transforming growth factor (TGF)-beta 1 gene sti mulated anchorage independent growth and promoted tumor growth, angiogenesi s, and metastasis after orthotopic implantation in severe combined immunode ficiency mice, In contrast, interleukin (IL)-10 transfected cells or cells cotransfected with these two genes exhibited reduced growth rates and signi ficantly reduced angiogenesis and metastasis after 8, 12, and 16 weeks. Enz yme-linked immunosandwich assays confirmed that the respective tumors expre ssed elevated levels of TGF-beta 1 and IL-10 in vivo. ELISAs further showed that TGF-beta 1 expression induced matrix metalloproteinases-2 (MMP-2) exp ression, 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-beta 1 and MMP-2 expression and inversely with IL-10 and TIMP-1 le vels. More importantly, mouse survival was zero after 4-6 months in mice be aring TGF-beta 1- and MMP-2-expressing tumors and increased significantly i n mice implanted with IL-10- and TIMP-1-expressing tumors (i.e., to >80% su rvival). Analysis of the metastatic lesions showed that they expressed TGF- beta 1 and MMP-2 but barely detectable levels of IL-10 or TIMP-1, suggestin g that IL-10 and TIMP-1 might normally block tumor growth, angiogenesis, an d metastasis.