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.
|Stearns, Mark E; Wang, Min (2011) Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors. Transl Oncol 4:147-56|
|Wang, Min; Hu, Youji; Amatangelo, Michael D et al. (2011) Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer. Mol Cancer Res 9:36-50|
|Stearns, Mark E; Amatangelo, Michael D; Varma, Devika et al. (2010) Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am J Pathol 177:3169-79|
|Goodyear, S M; Amatangelo, M D; Stearns, M E (2009) Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense. Prostate 69:689-98|
|Dolloff, Nathan G; Shulby, Shannon S; Nelson, Autumn V et al. (2005) Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. Oncogene 24:6848-54|
|Stearns, Mark; Tran, Jordan; Francis, Mary Kay et al. (2005) Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells. Cancer Res 65:2085-8|
|Shulby, Shannon A; Dolloff, Nathan G; Stearns, Mark E et al. (2004) CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells. Cancer Res 64:4693-8|
|Stearns, Mark E; Wang, M; Hu, Youji et al. (2003) Interleukin-10 activation of the interleukin-10E1 pathway and tissue inhibitor of metalloproteinase-1 expression is enhanced by proteasome inhibitors in primary prostate tumor lines. Mol Cancer Res 1:631-42|
|Wang, M; Hu, Y; Stearns, M E (2003) A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells. Br J Cancer 88:1605-14|
|Aoyagi, K; Shima, I; Wang, M et al. (1998) Specific transcription factors prognostic for prostate cancer progression. Clin Cancer Res 4:2153-60|
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