HOSTILE ENVIRONMENTS PROMOTE INVASION AND METATASIS

恶劣的环境促进入侵和转移

• 批准号: 7228204
• 负责人: Zaver M. Bhujwalla
• 金额: $ 27.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228204
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Arts; Basic Science; Biological Assay; Blood Vessels; Breast; Breast Cancer Cell; Cancer cell line; Cell Communication; Cell Extracts; Cell Line; Cells; Chemoprevention; Choline; Compatible; Condition; Cyclooxygenase Inhibitors; Data; Dependence; Development; Disease; Drug Delivery Systems; Endothelial Cells; Environment; Enzymes; Epithelial Cells; Exhibits; Generations; Human; Indomethacin; Inflammation; Inflammatory; Intervention; Invasive; Investigation; Lead; Liver; Lung; MCF7 cell; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Mammary Neoplasms; Mammary gland; Matrix Metalloproteinases; Mediating; Metabolic; Metabolism; Metastasis Suppressor Genes; Methods; Microscopy; Molecular Biology; NMR Spectroscopy; Neoplasm Metastasis; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Normal tissue morphology; Numbers; Outcome; PTGS2 gene; Pathway interactions; Permeability; Phenotype; Phospholipid Metabolism; Phospholipids; Phosphorylcholine; Physiological; Physiology; Play; Prevention; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Protein Overexpression; Proto-Oncogenes; Refractory; Reporting; Role; Small Interfering RNA; Solid Neoplasm; Spectrum Analysis; Stimulus; Stromal Cells; Survival Rate; System; Technology; Testing; Tetracycline; Tetracyclines; Toxic effect; Transgenic Organisms; Tumor Cell Line; Tumor Suppressor Genes; Tumor-Derived; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascularization; Work; autocrine; base; cancer cell; cancer therapy; clinically significant; cyclooxygenase 1; cyclooxygenase 2; in vivo; inhibitor/antagonist; knock-down; lipid metabolism; lymph nodes; macrophage; malignant breast neoplasm; matrigel; neoplastic cell; paracrine; prevent; tumor; tumor progression; vector

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.

描述（由申请人提供）： 在这次竞争性的更新申请中，我们继续保持对乳腺癌侵袭和转移的关注。转移性乳腺癌的存活率低得可怜，我们十年来的挑战仍然是寻找防止癌细胞扩散的方法。 在过去的四年里，我们进行了重要的观察，这使我们专注于了解环氧合酶-1和-2在乳腺癌侵袭和转移中的作用。第一个是抗炎非特异性 COX 抑制剂吲哚美辛可显着减少乳腺癌细胞侵袭。我们还发现，用吲哚美辛处理的侵袭性乳腺癌细胞的胆碱磷脂代谢恢复为非恶性细胞系更典型的胆碱磷脂表型。此外，我们观察到 COX-1 的表达随着恶性进展而增加。这些观察结果使我们提出了三个新假设：（1）与野生型或载体转染的对照细胞和肿瘤相比，COX-1和COX-2过表达细胞和实体瘤中通过MRS和MRI检测到的磷酸胆碱以及血管体积和通透性更高。 COX-1和COX-2表达增加会导致侵袭和转移增加； (2)COX-1和COX-2减少会减少侵袭和转移。在细胞和实体瘤的 MRS 和 MRI 研究中将检测到磷酸胆碱以及血管体积和渗透性的下降； (3)癌细胞分泌的旁分泌因子可能主要源自环氧合酶活性，其显着改变内皮细胞-癌细胞相互作用，并在促进实体瘤炎症诱导条件的侵袭和转移中发挥重要作用。在这一竞争性更新应用中，我们将使用最先进的无创磁共振 (MR) 成像 (I) 和光谱 (S) 方法，以及利用 siRNA 技术的分子生物学方法来测试这些假设。环氧合酶 COX-1 和 -2 从花生四烯酸合成 PG。肿瘤细胞或肿瘤相关宿主细胞（如巨噬细胞、内皮细胞和基质细胞）产生的前列腺素（PG）长期以来一直被认为在动物和人类肿瘤的进展和转移中发挥刺激作用。本申请中提出的研究将有助于确定预防转移性疾病的靶点和途径。