Reich R, Martin G R
Department of Pharmacology, Hebrew University of Jerusalem, Israel.
Prostaglandins. 1996 Jan;51(1):1-17. doi: 10.1016/0090-6980(95)00154-9.
Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.
转移是一个复杂的过程，几乎是一个级联反应，涉及多个步骤和活动。然而，一个重要因素是恶性细胞能够穿透围绕组织、血管、神经和肌肉的多层基底膜屏障，否则这些屏障会阻止它们的扩散。恶性肿瘤细胞穿透基底膜是一个需要蛋白水解作用的活跃过程。我们在此报告，花生四烯酸代谢的环氧化酶和脂氧化酶途径的抑制剂通过减少MMP-2的产生，将小鼠黑色素瘤细胞和人纤维肉瘤细胞转变为非侵袭性状态，MMP-2是一种降解基底膜所需的酶。每条途径的特定代谢产物，即PGF2α和5-HPETE，能够克服这种阻断并恢复胶原酶的产生、体外侵袭性和体内转移活性。这些研究表明花生四烯酸代谢产物在转移中起关键作用，并提示了抑制癌症扩散的新治疗方法。
