HOSTILE ENVIRONMENTS PROMOTE INVASION AND METATASIS

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): In this competitive renewal application, we continue to maintain our focus on breast cancer invasion and metastasis. Metastatic breast cancer has pitifully low survival rates, and the challenge of our decade continues to be to find ways to prevent cancer cells from disseminating. With the past four years we made key observations, which have led us to focus on understanding the role of cyclooxygenase-1 and -2 in breast cancer invasion and metastasis. The first was that the anti-inflammatory nonspecific COX inhibitor, indomethacin, significantly reduced breast cancer cell invasion. We also found that the choline phospholipid metabolism of invasive breast cancer cells treated with indomethacin reverted towards a choline phospholipid phenotype more typical of a nonmalignant cell line. Additionally, we observed an increased expression of COX-1 with malignant progression. These observations have led us to formulate three new hypotheses: (1) Phosphocholine and vascular volume and permeability detected by MRS and MRI will be higher in COX-1 and COX-2 overexpressing cells and solid tumors compared to wild type or vector transfected control cells and tumors. Increased expression of COX-1 and COX-2 will result in an increase in invasion and metastasis; (2) Decreased COX-1 and COX-2 will decrease invasion and metastasis. A decrease in phosphocholine and vascular volume and permeability will be detected in the MRS and MRI studies of cells and solid tumors; (3) Cancer cells secrete paracrine factors which may primarily be derived from cyclooxygenase activity which significantly alter endothelial cell-cancer cell interactions and play a significant role in promoting invasion and metastasis from inflammation inducing conditions in solid tumors. In this competitive renewal application we will use state of the art noninvasive magnetic resonance (MR) imaging (I) and spectroscopy (S) methods, and molecular biology approaches utilizing siRNA technology to test these hypotheses. The cyclooxygenase enzymes COX-1 and -2 synthesize PGs from arachidonic acid. Prostaglandins (PGs) produced by tumor cells or tumor-associated host cells such as macrophages, endothelial cells and stromal cells have long been known to play a stimulating role in progression and metatases of animal and human tumors. The studies proposed in this application will lead to the potential identification of targets and pathways for the prevention of metastatic disease.