The colony stimulating factor-1 (CSF-1) receptor (CSF-IR) kinase instructs multipotent hematopoietic cells to adopt a macrophage fate and regulates the functions of differentiated cells. Previous results from this program have shown that CSF-1-driven tumor-associated macrophages (TAMs) regulate angiogenesis, carcinoma cell invasion, intravasation and metastasis in mouse models of breast cancer. TAM production of angiogenic factors and cytokines, TAM migration and TAM promotion of carcinoma cell migration have been identified as important CSF-1 R-mediated events. Our analysis of macrophage CSF-IR phosphotyrosyl (pTyr) signaling pathways has shown that CSF-1 R pTyr pathways control CSF-1-regulated proliferation, whereas other pTyr pathways regulate differentiation, morphology and motility. In particular, we have shown that the pTyr-721 pathway is critical for the paracrine interaction between macrophages and carcinoma cells in vitro and for macrophage motility within the tumor in vivo, for the production of angiogenic factors and for the release of EGF that participates in a paracrine loop to activate tumor cell invasiveness. Thus we hvpothesize that the CSF-IR pTyr-721 signaling pathways function in TAMs to regulate TAM promotion of carcinoma cell progression and metastasis. The overall aim of Proiect 2 is to confirm this by direct in vivo analysis, to determine when and where macrophage enhancement of tumor progression mediated by CSF- 1R pTyr-721 signaling is occurring and to identify the downstream pathways involved. To test this hypothesis, we propose a comprehensive approach involving three specific alms. In the first aim, we will establish the in vivo roles of CSF-1 R pTyr-721 signaling in mouse mammary tumor progression and metastasis using novel imaging approaches. In the second aim, CSF-IR pTyr-721-dependent signaling molecules and macrophage-produced cytokines that have been identified using combination of approaches will be examined in vitro using newly developed assays that accurately mimic the paracrine interaction and TAM-mediated tumor cell Intravasation and extravasation. In the third aim, molecules selected on the basis of these in vitro functional assays will be examined for their in vivo roles In tumor progression and metastasis. Their clinical significance will be determined by immunohistochemistry of human CDP Breast Cancer Progression Tissue Microarrays (TMA) and using patient samples in collaboration with Project 5. These studies are expected to provide in vivo data concerning the function of selected signaling molecules that act in CSF-IR downstream signaling pathways in TAMs to effect tumor progression and metastasis.
The results of the proposed work will enhance our understanding of why anti-inflammatory drugs (e.g. CSF-IR inhibitors) are protective against cancer incidence and progression and are expected to provide in vivo data concerning the function of signaling molecules that act in TAMs to effect tumor progression and metastasis. They are also expected to lead to the identification of new targets for diagnostic tests in man and to preclinical studies testing novel therapeutic approaches.
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