TUMOR CELL-DESMOPLASTIC RESPONSE INTERACTIONS

促结缔组织增生对肿瘤侵袭的反应是一个知之甚少的 宿主成肌纤维细胞介导胶原反应 许多人类癌症的“硬块”外观。 最近 观察表明，反应发挥了重要作用， 对肿瘤侵袭转移的抑制作用 高肌纤维母细胞分泌金属蛋白酶抑制活性。 然而，这种反应未能完全阻止入侵， 转移 这项研究职业发展奖的建议将 深入研究这些肿瘤金属蛋白酶的性质， 促纤维增生抑制剂的相互作用，最终影响 转移 目标#1将检查 肌成纤维细胞源性金属蛋白酶抑制剂活性存在 促结缔组织增生反应（DIMP）。 因为大多数组织 不抵抗入侵，但含有普遍存在的组织抑制剂 金属蛋白酶（TIMP），这一目标将涉及一个详细的 DIMP与TlMP关于可能参数的比较 （IV型和I型的摩尔抑制活性增加） 胶原酶，合成速率增加， 亲和力），这可以解释DIMP对 抗肿瘤侵袭 目标#2将检查可能的 肿瘤细胞胶原酶与DIMP相互作用的机制 这将使一些肿瘤细胞能够成功地 即使在存在大量过量的胶原蛋白的情况下， 促结缔组织增生金属蛋白酶抑制活性。 目标#3将 检查促结缔组织增生性反应， 成功地抑制了肿瘤的侵袭， 选择压力更大的肿瘤。 组织增生 应答选择的亚系将来自肺 转移和几种相关的转移表型 特征检查。

The desmoplastic response to tumor invasion is a poorly understood host myofibroblast-mediated collagenous response responsible for the "hard lump" appearance of many human cancers. Recent observations have suggested that the response exerts significant inhibitory effects on tumor invasion and metastasis mediated by high myofibroblast-secreted metalloproteinase inhibitory activity. The response fails, however, to totally block invasion and metastasis. This research career development award proposal will focus in depth on the nature of these tumor metalloproteinase- desmoplastic inhibitor interactions which ultimately influence metastasis. Aim #1 will examine the uniqueness of the myofibroblast-derived metalloproteinase inhibitor activity present within the desmoplastic response (DIMP). Since most tissues are not resistant to invasion yet contain ubiquitous tissue inhibitors of metalloproteinases (TIMP), this aim will involve a detailed comparison of DIMP with TlMP with respect to possible parameters (increased molar inhibitory activity of Type IV and Type I collagenase, increased rate of synthesis, and increased tissue affinity) which could account for DIMP's selective contribution to tumor invasion resistance. Aim #2 will examine a possible mechanism of interaction between tumor cell collagenase and DIMP which would allow some tumor cells to carry out successful collagenolysis and invasion even in the presence of a vast excess of desmoplastic metalloproteinase inhibitory activity. Aim #3 will examine whether the desmoplastic response, being only partially successful in inhibiting tumor invasion, ultimately exerts selection pressure for a more aggressive tumor. Desmoplastic response-selected sublines will be derived from pulmonary metastases and several of their relevant metastatic phenotypic features examined.