THE DESMOPLASTIC RESPONSE TO TUMOR INVASION

对肿瘤侵袭的促纤维化反应

• 批准号: 3179897
• 负责人: Sanford Howard Barsky
• 金额: $ 9.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3179897
• 关键词: breast neoplasms; chemotaxis; collagenase; growth factor; human tissue; hydroxyproline; immunofluorescence technique; ion exchange chromatography; metastasis; neoplasm /cancer invasiveness; neoplastic cell; plasminogen activator

The desmoplastic response to tumor invasion is an important though poorly understood collagenous host reaction responsible for the hard lump appearance of many cancers. In human breast carcinoma, approximately 80% of cases are associated with intense desmoplasia, a response which promotes early clinical detection. Both the mechanism of this response and its effect on tumor invasion and metastasis are not known, but previous studies have indicated that the desmoplastic reaction is composed of numerous host myofibroblasts and a unique collagen profile with relatively high amounts of Type V collagen. The aims of this research project are three-fold. The first aim is to characterize and purify a myofibroblast growth factor elaborated by invasive tumor cells. Human breast carcinoma tissue of the desmoplastic variety and cell lines such as MCF-7 and MDA-MB-134-VI will be studied for the presence of such factors by chemotaxis, mitogenesis, and myofibroblast-differentiating assays. Non-desmoplastic human breast carcinoms (medullary type) and cell lines derived from them will serve as controls. The second aim is to further characterize the desmoplastic response biochemically, specifically identifying inhibitors to tumor proteases such as Type IV collagenase, cathepsins, and plasminogen activator, all of which have been implicated in the invasive process. Human breast carcinoma tissue of the desmoplastic variety again will serve as source from which to extract these inhibitors to invasion. The demonstration of high amounts of protease inhibitors within desmoplastic tissue would suggest that one purpose of the response is to limit the local spread of tumor. The final aim of this study is to examine the effect of the desmoplastic response on distant metastasis. To achieve this, a new quantitative model of desmoplasia has been developed in the C57 BL/6 mouse, utilizing the syngeneic transplantable tumor, BL6 melanoma, and 14C proline instilled intraperitoneally. Host collagen synthesis is measured at the primary site and perturbated with blockers of collagen synthesis. The effect on pulmonary metastases will be determined. The long-term purpose then is insight into the mechanism and meaning of desmoplasia. (A)

对肿瘤侵袭的促纤维增生反应虽然很差但很重要 了解导致硬块的胶原宿主反应 许多癌症的出现。 在人类乳腺癌中，大约 80% 的病例与强烈的结缔组织增生有关，这种反应促进 早期临床检测。 这种反应的机制及其 对肿瘤侵袭和转移的影响尚不清楚，但之前的研究 已经表明促纤维增生反应是由许多主体组成的 肌成纤维细胞和含量相对较高的独特胶原蛋白 V型胶原蛋白。 该研究项目的目标有三个。 这 第一个目标是表征和纯化肌成纤维细胞生长因子 由侵袭性肿瘤细胞精心制作。 人乳腺癌组织 促纤维增生品种和细胞系，如 MCF-7 和 MDA-MB-134-VI 将被 通过趋化性、有丝分裂发生和研究这些因素的存在 肌成纤维细胞分化测定。 非促纤维增生人类乳房 癌（髓质型）和源自它们的细胞系将作为 控制。 第二个目标是进一步表征促纤维塑性 生化反应，特异性识别肿瘤抑制剂 蛋白酶，例如 IV 型胶原酶、组织蛋白酶和纤溶酶原 激活剂，所有这些都与侵入过程有关。 促纤维增生型人类乳腺癌组织将再次发挥作用 作为提取这些入侵抑制剂的来源。 这 促结缔组织中含有大量蛋白酶抑制剂 组织表明，响应的目的之一是限制局部 肿瘤扩散。 本研究的最终目的是检验 对远处转移的促纤维增生反应。 为了实现这一目标，一个新的 已在 C57 BL/6 小鼠中开发出结缔组织形成的定量模型， 利用同基因可移植肿瘤、BL6 黑色素瘤和 14 C 腹腔滴注脯氨酸。 测量宿主胶原蛋白合成 在主要部位并用胶原蛋白合成阻滞剂扰乱。 将确定对肺转移的影响。 长期来看 目的是深入了解结缔组织增生的机制和意义。 （一个）