Control of Tumor Growth by the MMP/Angiostatin Pathway

血管生成对于肿瘤生长是必不可少的，并且阻断该过程被视为治疗肿瘤的有效工具。 控制癌症的生长。我们发现在整合素l缺失的小鼠中， 与野生型小鼠相比。这种减少是由于在哺乳动物中基质金属蛋白酶（MMP）的过度表达。 A1-无效和随后的血管抑制素（一种内皮细胞生长抑制剂）的产生 纤溶酶原我们的研究结果与公认的MMPs促肿瘤作用相反，表明 MMPs的过量合成可能对肿瘤生长起相反的作用。一方面，MMPs的增加可能 通过诱导细胞外基质降解促进细胞迁移和转移。另一方面，在一项研究中， 增加的MMPs可以通过血管抑素的产生来防止肿瘤生长。我们发现抑制MMP 体内表达导致血管抑制素合成减少和随后肿瘤生长增加， 血管化这一观察结果，连同MMP抑制剂在肿瘤中所取得的令人失望的结果， 治疗人类癌症，表明MMP抑制剂用作抗肿瘤药物可能实际上会导致 通过阻止肿瘤生长抑制剂的产生， 内皮细胞生长。此外，我们还发现整合素otl直接参与了 细胞增殖，表明该受体可能与MMP/血管抑素一起发挥协同作用 轴通过直接调节内皮细胞增殖。整合素o_1与基质金属蛋白酶/血管抑素的关系 将在以下目标中探索肿瘤进展的轴。1)i）在体内分析的作用 MMP/血管抑素轴在控制原发性与转移性人类肿瘤中的作用，ii）MMP抑制剂是否可以 可成功用于预防原发性与转移性癌症。II）区分直接 整合素c_l在控制内皮细胞增殖中的作用以及基质金属蛋白酶或血管抑素对内皮细胞增殖的影响 将α 1缺失小鼠与纤溶酶原或MMP缺失小鼠杂交。III）真实的时间分析效果 血管抑素和MMP抑制剂对肿瘤血管形成的影响。 这些研究将帮助我们确定MMP/血管抑素轴的调节如何被用作一种工具， 以特异性抑制肿瘤血管形成和生长。

Angiogenesis is essential for tumor growth and blocking this process is viewed as a valid tool for the control of cancer growth. We showed that in integrin _l-null mice tumor angiogenesis is reduced compared to that of wild type mice. This reduction is due to overexpression of matrix metaUoproteinases (MMPs) in the al-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from plasminogen. Our findings, in contrast to the accepted role of MMPs being pro-tumorigenic, suggest that excess synthesis of MMPs may play opposite effects on tumor growth. On one hand, increased MMPs may promote cell migration and metastasis by inducing extracellular matrix degradation. On the other hand, increased MMPs may prevent tumor growth via angiostatin generation. We showed that inhibition of MMP expression in vivo leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. This observation, together with the disappointing results achieved by MMP inhibitors in the treatment of human cancers, suggests that MMP inhibitors used as anti-tumor drugs might in fact cause a paradoxical increase in tumor growth and angiogenesis by preventing the generation of inhibitors of endothelial cell growth. In addition, we also showed that integrin otl is directly involved in the control of cell proliferation suggesting that this receptor may play a synergistic role together with the MMP/angiostatin axis by directly regulating endothelial cell proliferation. The role of integrin o_1 and the MMP/angiostatin axis in tumor progression will be explored in the following aims. 1) Analyze in vivo i) the role of the MMP/angiostatin axis in the control of primary vs. metastatic human tumors, ii) whether MMP inhibitors can be successfully used in the prophylaxis of primary vs. metastatic cancers. II) Distinguish between a direct role of integrin c_l in the control of endothelial cell proliferation and the effect of MMPs or angiostatin by crossing the otl-null mice with the plasminogen- or MMP-null mice. III) Analyze in real time the effect of angiostatin and MMP inhibitors on tumor vascularization using the cutaneous window assay. These studies will help us to determine how stinaulation of the MMP/angiostatin axis can be used as a tool to inhibit specifically tumor vaseularization and growth.