Public reporting burden for this collection of information is estinated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and rniantaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estinate or any other aspect of this collection of infonration, nlduding suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports. 1215 Jefferson Davis Highway, Suite 1204. Arlington, VA 22202-4302, and to the Office of Management and Budget, breast cancer cells and THP-1 macrophages as a model of epithelial cell-stromal cell interaction in breast cancer progression. THP-l macrophages enhanced the proliferation of MCF-7 cells, protected them against tamoxifen killing, and induced the expression of several MCF-7 angiogenesis-related genes, including IL-8 (interleukin-8), OPN (osteopontin), MDK (Midkine), TGFR1/2/3 (TGF receptors 1, 2, 3), and ID3 (inhibitor of differentiation 3).Pre-treatment of THP-l macrophages with 1 mM aspirin abrogated their protection of MCF-7 cells against tamoxifen killing, while down-regulating several angiogenesis-related genes in the macrophages. Reciprocally, MCF-7 cells altered the expression of angiogenesis-related genes in the macrophages: THP-l macrophages expressed both vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) genes when cultured alone; however, in the presence of MCF-7 cells, PEDF expression was dramatically down-regulated. Because PEDF is a potent inhibitor of angiogenesis, the ability of MCF-7 cells to suppress PEDF expression in tumor-associated macrophages, while sustaining VEGF expression, may be a mechanism by which tumor cells regulate macrophage function to promote tumor growth.
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INTRODUCTIONAccumulating evidence suggests that monocytes and macrophages are recruited to tumors where, in response to microenvironmental stimuli, they secrete inflammatory products, growth factors, and angiogenic cytokines that may promote tumor growth and metastasis (1). Macrophages may constitute as much as half of the mass of cells in some tumors, including breast tumors, and their presence has been shown to correlate with a poor prognosis (2). The critical role of monocytes and macrophages in angiogenesis has been exemplified by the identification of thymidine phosphorylase (TP), a known angiogenic factor, as a monocyte or macrophage product. TP has long been associated with the propensity for angiogenic growth, but its mechanism of action has been elusive. Recently, it was shown that a dephosphorylated product of the TP reaction, 2-deoxyribose (2-dR), is a chemoattractant for vascular endothelial cells (EC) (3). Tumor-associated macrophages produce 2-dR which recruits vascular ECs; under the influence of stromal cell-derived cytokines, these ECs form a tumor vasculature. Macrophage involvement in tumor initiation and progression is further supported by th...
