HOSTILE ENVIRONMENTS PROMOTE INVASION AND METATASIS

描述（由申请人提供）： 在这一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，我们这十年的挑战仍然是找到防止癌细胞扩散的方法。 在过去的四年里，我们进行了关键的观察，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。第一个是抗炎的非特异性考克斯抑制剂吲哚美辛显著降低了乳腺癌细胞的侵袭。我们还发现，侵袭性乳腺癌细胞的胆碱磷脂代谢与吲哚美辛治疗恢复到一个胆碱磷脂表型更典型的非恶性细胞系。此外，我们观察到考克斯-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的假设：（1）与野生型或载体转染的对照细胞和肿瘤相比，在考克斯-1和考克斯-2过表达的细胞和实体瘤中，通过MRS和MRI检测的磷酸胆碱和血管体积和渗透性将更高。考克斯-1和考克斯-2表达增加，浸润和转移增加;（2）考克斯-1和考克斯-2表达减少，浸润和转移减少。在细胞和实体瘤的MRS和MRI研究中将检测到磷酸胆碱和血管体积和渗透性的降低;（3）癌细胞分泌旁分泌因子，其可能主要来源于环加氧酶活性，其显著改变内皮细胞-癌细胞相互作用，并在促进实体瘤中炎症诱导条件的侵袭和转移中起重要作用。在这项竞争性更新申请中，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。环氧合酶考克斯-1和-2从花生四烯酸合成PG。由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）长期以来被认为在动物和人类肿瘤的进展和转移中起刺激作用。本申请中提出的研究将导致潜在的识别用于预防转移性疾病的靶点和途径。

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.