We postulate, based on preliminary studies, that the IL-10/IL-10R axis controls a 'lymphangiogenesis switch' leading to microvessel formation and the transformation of tumors from 'latent cancers' to actively growing cancers, which exhibit localized metastases to the perineural fibers and lymph nodes.. In this grant application, the overall goal is to assess whether IL-10 selectively targets lymphangiogenesis (and/or angiogenesis) to block microvessel formation, prostate tumor growth and localized metastases by primary prostate tumor sublines, HPCA-10a, 10b, 10c, 10d, 10e and 10f. The goals are three foal, including:
Aim 1 a: to characterize the IL-10R axis signaling pathway, which down regulates VEGF D synthesis;
Aim 1 b: to evaluate the role of the IL-10 receptor axis in controlling VEGF D/VEGF C expression in primary tumor cell lines and tumor explants;
Aim lc: to determine the influence of IL-10 on tumor cell induced lymphangiogenesis (and angiogenesis) in vitro.
Aim 2. To test whether IL-10 transfection blocks IL-10S1- VEGF D signaling and VEGF D and VEGF C expression to prevent lymphangiogenesis and/or angiogenesis, and localized metastases in an orthotopic SCID mouse model.
Aim 3 : to evaluate the expression by immunoassays of the genes/proteins regulated by the IL-10R axis, which are associated with lymphangiogenesis (and angiogenesis) in human prostate tumor studies. The labeling studies will be done with 'tissue arrays' blocks generated from approximately 1294 prostate cancer specimens and approximately 400 biopsies (e.g. including archival material collected over the past 5 yrs), plus fresh frozen sections of whole mount prostates. We will compare the expression profiles relative to the pathology of putative 'latent' cancers, and malignant cancers as well as localized metastases to the lymph nodes, neural, muscle, and seminal vesicles. Lymphatic and blood microvessel distributions will be measured by immunolabeling with LYVE-1, Podoplanin and Factor VIII antibodies. A 3-D reconstruction imaging software program termed ACIS will be employed for measuring microvessel density in serial sections. Evaluation of the data with respect to the pathology and patient outcome over a 5-10 yr period will permit evaluation of the importance of gene expression profiles. Overall, the studies should demonstrate whether the IL-10R axis and down stream effector genes (and specifically IL-10S1-VEGF D, and VEGF D) play a pivotal role in lymphangiogenesis and/or angiogenesis processes.
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