Survival rates for metastatic breast and other cancers remain pitifully low and, barring a discovery to prevent cancer or cure it, the challenge of our decade is surely to find ways to prevent cancer cells from disseminating. Divested of this aspect, cancer ceases to be life-threatening particularly for the breast. Compelling evidence suggests that trauma or physiologically unfavorable 'hostile' environments promote metastasis. In this proposal we will use state of the art noninvasive magnetic resonance (MR) imaging (I) and spectroscopy (S) methods to test the hypothesis that a hostile physiological environment with low pH, oxygen and glucose promotes invasion and metastasis of human breast cancer cells. Studies will be performed on three human breast cancer cell lines (MDA-MB-435, MDA-MB-231 and MCF-7) and a hyperplastic human breast cell line (MCF-12A) preselected for differences in invasive and metastatic behavior. A specially designed invasion assay ('Metabolic Boyden Chamber' assay) adapted for noninvasive MR studies will be used to (i) probe metabolism during carefully controlled modulation of the physiological environment and (ii) simultaneously measure invasion or migration of cells through reconstituted basement membrane. A hostile environment will be induced within orthotopic solid tumors derived from the human breast cancer lines (MDA-MB-435, MCF-7) to determine if incidence of metastasis increases after physiological trauma and to identify vascular, metabolic and physiological changes associated with the trauma which play a role in this promotion. To stimulate a clinical situation, the stromal bed around the mammary fat pad will be irradiated before inoculation of breast cancer cells. The impact of tumor bed irradiation on the physiology/metabolism of the stromal tissue, the vascular characteristics of tumors growing in the pre-irradiated bed, and the increase in the incidence of metastasis will be determined. Cells and tissues typically respond to injury with inflammation which results in the secretion of eicosanoids which play a role in cell invasion and metastasis. The ability of anti-inflammatory agents to attenuate or eliminate the invasive metastatic behavior of breast cancer cells under normal and stressful conditions, and the effects of these agents on cell physiology and metabolism will be determined. The proposed studies will identify physiological and metabolic characteristics which promote invasion and metastasis and open avenues of treatment to prevent metastasis. Several existing forms of treatment induce hostile environments and it is imperative to determine if these treatments promote subsequent metastasis by promoting invasive behavior of residual cancer cells.
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