BIOLOGY OF SOLID TUMOR GROWTH AND IMMUNE REJECTION

实体瘤生长和免疫排斥的生物学

• 批准号: 3168149
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 15.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-02-01 至 1988-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3168149
• 关键词: Hodgkin's disease; anticoagulants; autoradiography; biliary tract neoplasm; breast neoplasms; chemoattractants; electron microscopy; fibrin; fibrinolytic agents; host neoplasm interaction; immunochemistry; immunofluorescence technique; immunopathology; leukocytes; macrophage; malignant ascites; mathematical model; migration inhibition factor; neoplasm /cancer blood supply; neoplasm /cancer immunology; neoplasm /cancer pharmacology; neoplasm /cancer remission /regression; neoplasm /cancer transplantation; neoplastic cell; neoplastic growth; radiation detector; radiotracer; tissue /cell culture

The goal of this research has been to evaluate the role of fibrin deposition and turnover in the biology of tumor growth, particularly with reference to tumor stroma formation. In the past year we have completed initial studies concerning the quantitation of fibrinogen influx and fibrin deposition and turnover in two well-characterized guinea pig carcinomas, line 1 and line 10 bile duct tumors. Earlier immunofluorescence studies revealed fibrin deposits in both tumors (line 1 much greater than line 10). In accord with these data, trace-labeled guinea pig fibrinogen (GPF) accumulated in both tumors in amounts that matched or exceeded plasma fibrinogen levels. However, line 1 tumor GPF content was four times that of line 10 tumors and 11 to 33 times that of normal subcutaneous tissue. The great bulk of accumulated GPF was in the form of cross linked (transglutaminated) fibrin. Because initial influx of fibrinogen into tumors and clotting were identical for both tumors, the large differences in GPF accumulation (line 1 greater than line 10) apparently reflect differences in fibrinolysis. Other studies have been concerned with the nature and importance of tumor-associated procoagulants to tumor fibrin deposition. Several tumor procoagulant activities have been identified in both the intrinsic and extrinsic coagulation pathways, as well as provision of a surface for prothrombinase generation, the penultimate step in the common coagulation pathway and one essential for clotting to proceed to completion. However, our studies in the past year have shown that tumor-associated procoagulants may be very much less important than had been thought earlier. We found that increased microvascular permeability alone is sufficient to induce equivalant extravascular coagulation in several normal tissues. The results indicate that saturating levels of procoagulant are present even in normal tissues in association with normal connective tissue cells. Therefore, the level of microvascular permeability becomes the rate limiting step in extravascular coagulation for solid tumors and also for a broad spectrum of inflammatory reactions. (A)

这项研究的目的是评估纤维蛋白的作用 肿瘤生长生物学中的沉积和周转，特别是在 参考肿瘤间质的形成。在过去的一年里，我们完成了 纤维蛋白原内流和纤维蛋白定量的初步研究 在两个特征良好的豚鼠癌中沉积和周转， 1、10行胆管肿瘤。早期免疫荧光研究 两种肿瘤均可见纤维蛋白沉积(第1行远大于第1行 10)。根据这些数据，示踪标记的豚鼠纤维蛋白原(GPF) 在两种肿瘤中积聚的量与血浆相当或超过血浆 纤维蛋白原水平。然而，第1行肿瘤的GPF含量是 10系肿瘤，是正常皮下组织的11~33倍。 大量积累的GPF以交联体的形式存在 (转谷氨酰胺)纤维蛋白。因为纤维蛋白原最初流入 两种肿瘤的肿瘤和凝血是相同的，最大的区别是 在GPF累加(行1大于行10)中明显反映 纤溶方面的差异。 其他研究一直关注的是 肿瘤相关促凝剂对肿瘤纤维蛋白沉积的影响。几种肿瘤 促凝血剂活性已经在内源性和 外源性凝血途径，以及为 凝血酶原酶的产生，普通凝血的倒数第二步 这是一条重要的途径，也是凝血完成所必需的。然而， 我们在过去一年的研究表明，与肿瘤相关的促凝剂 可能比之前认为的要重要得多。我们发现 仅微血管通透性的增加就足以导致 在几个正常组织中相当于血管外凝血。这个 结果表明，促凝血剂的饱和水平即使在 正常组织与正常结缔组织细胞相关。 因此，微血管通透性水平就变成了 实体肿瘤血管外凝固术的限制步骤 广泛的炎症反应。(A)