TUMOR CELL-DESMOPLASTIC RESPONSE INTERACTIONS

促结缔组织增生对肿瘤侵袭的反应还知之甚少。 宿主肌成纤维细胞介导的胶原反应 许多人类癌症的“硬肿块”现象。近期 观察表明，这种反应对 抗肿瘤侵袭转移作用的实验研究 高肌成纤维细胞分泌的金属蛋白酶抑制活性。 然而，回应未能完全阻止入侵和 转移。这项研究职业发展奖的提议将 深入研究这些肿瘤金属蛋白酶的性质- 促结缔组织抑制物相互作用最终影响 转移。目标#1将检查以下内容的唯一性 肌成纤维细胞衍生的金属蛋白酶抑制物活性存在 在促结缔组织反应(DIMP)内。因为大多数组织都是 不抵抗入侵，但含有无处不在的组织抑制物 金属蛋白酶(TIMP)，这一目标将涉及详细的 关于可能参数的DIMP和TLMP的比较 (IV型和I型的摩尔抑制活性增加 胶原酶，合成速度加快，组织增多 亲和力)，这可能解释了DIMP对 肿瘤侵袭性抵抗。目标#2将研究一种可能的 肿瘤细胞胶原酶与DIMP相互作用机制的研究 这将允许一些肿瘤细胞成功地进行 胶原分解和侵袭，即使在存在大量过剩的情况下也是如此 促结缔组织金属蛋白酶抑制活性。目标#3将 检查促结缔组织反应是否只是部分的 成功抑制肿瘤侵袭，最终发挥作用 更具侵袭性的肿瘤的选择压力。促结缔组织 响应-选定的子行将派生自肺 转移瘤及其相关的几种转移表型 检查过的特征。

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.