Colony stimulating factor-1 (CSF-1) is the primary growth factor regulating macrophage survival, proliferationand differentiation as well as morphology, adhesion and motility. CSF-1 regulation of macrophages plays animportant role in enhancing the progression and metastasis of solid tumors. CSF-1 expression and thepresence of tumor-associated macrophages (TAMs) in human breast cancer are correlated with poorprognosis. Mammary tumor metastases are severely reduced in the macrophage-depleted CSF-1-deficient(Csf-1op/Csf-1op) mouse. Furthermore, in mouse models of breast cancer, TAMs, angiogenesis, metastasisand intravasation can be reduced and the life of tumor bearing mice prolonged by removing CSF-1, orblocking the CSF-1 R. Previous studies of this Program have demonstrated the existence of a paracrineinteraction between TAMs and carcinoma cells necessary for the promotion of invasion of mammary tumorcells in mice and suggest that CSF-1 exerts these effects by regulating macrophage chemotaxis and thesecretion of angiogenic and tumor cell chemotactic factors. In this project it is proposed to study themolecular mechanisms of signaling from the CSF-1 receptor that regulate these processes. The rationale forthe proposed studies is that an understanding of the molecular mechanisms involved will provide noveltherapeutic targets in breast cancer.Preliminary experiments indicate that the signaling pathways downstream of CSF-1 R Y721 and Y706phosphorylation, respectively positively and negatively regulate macrophage motility and tumor cell invasionin vitro. The overall aim of the proposal is to elucidate the signaling pathways that regulate macrophagemotility and tumor cell invasion and to identify the angiogenic and tumor cell chemotactic factors produced bymacrophages and to evaluate their significance for tumor progression and metastasis.
The specific aims are:
Aim 1 : To define CSF-1 receptor pY721-based signaling pathways that enhance macrophage chemotaxis.
Aim 2 : To identify the tumor cell chemotactic and angiogenic factors synthesized and secreted bymacrophages and the CSF-1 R phosphotyrosine signaling pathways regulating their production.
Aim 3 : To determine the significance of identified CSF-1 chemotactic signaling pathways and macrophagetumor cell chemotactic and angiogenic factors in tumor progression and metastasis.Relevance to public health: Breast cancer is the leading cancer of women. Previous studies have shown thatparticular non-tumor cells (TAMs) in the tumor microenvironment enhance tumor progression andmetastasis. This project focuses on identifying the underlying mechanisms of this enhancement with the goalof identifying novel therapeutic targets.
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