Inhibition of tumor-cell attachment to extracellular matrix as a method for preventing tumor recurrence in a surgical wound.
Inhibition of tumor-cell attachment to extracellular matrix as a method for preventing tumor recurrence in a surgical wound.
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抑制肿瘤细胞与细胞外基质的附着作为预防手术伤口肿瘤复发的方法。
作者：
G. Whalen;D. Ingber
对四种不同的可移植小鼠肿瘤的研究表明，接触肿瘤块污染的手术器械可能在手术伤口产生肿瘤。被看不见的污染剪刀割伤的小鼠中，87%的小鼠患上了肿瘤。用水灌溉不能阻止肿瘤生长。在溢出的肿瘤细胞侵入并在伤口部位复发之前，它们必须首先附着在潜在的细胞外基质上。我们设计了一种简单的体外试验来鉴定肿瘤细胞附着抑制剂，以开发可以防止肿瘤细胞再植入的治疗性化合物。各种测试化合物，包括蛋白酶（胰蛋白酶和色散酶），已知的基质代谢调节剂（脯氨酸类似物，环己亚胺，肝素，可的松，可的龙，肝素类固醇组合），大分子质量聚合物（琼脂糖，葡聚糖，聚乙烯氧化物）和合成纤维连接蛋白肽，测试了它们抑制小鼠黑色素瘤（B16-F10）细胞粘附在糊化培养液上的能力。当细胞置于含血清的培养基中时，大多数化合物对肿瘤细胞粘附作用很小或没有影响。然而，我们发现了三种以可逆方式抑制肿瘤细胞附着的化合物：(1)胶原沉积的特异性抑制剂（l -氮杂啶-2-羧酸）；(2)细菌中性蛋白酶（disase）；(3)合成含有负责细胞结合的精氨酸-甘氨酸-天冬氨酸（RGD）序列的纤维连接蛋白肽。消酵素和含rgd的多肽也能抑制细胞植入，防止手术伤口中肿瘤的形成。我们建议，附着抑制剂可以单独使用或与其他生物修饰剂一起使用，以在手术时阻止游离肿瘤细胞的植入，从而防止局部肿瘤复发。
Studies with four different transplantable murine tumors demonstrated that surgical instruments contaminated by contact with a tumor mass could produce tumors in a surgical wound. Eighty-seven per cent of mice with wounds made by invisibly contaminated scissors developed tumors. Irrigation with water did not prevent tumor growth. Before spilled tumor cells can invade and grow into a recurrence in the wound site, they must first attach to underlying extracellular matrix. We have devised a simple in vitro assay to identify inhibitors of tumor-cell attachment to develop therapeutic compounds that can prevent tumor-cell reimplantation. Various test compounds, including proteases (trypsin and Dispase), known modulators of matrix metabolism (proline analogues, cycloheximide, heparin, cortisone, cortexolone, and heparin-steroid combinations), large molecular weight polymers (agarose, dextran, polyethylene oxide), and synthetic fibronectin peptides were tested for their ability to inhibit mouse melanoma (B16-F10) cell attachment to gelatinized dishes. Most of these compounds had little or no effect on tumor-cell adhesion when cells were plated in serum-containing medium. However we identified three compounds that inhibited tumor-cell attachment in a reversible fashion: (1) a specific inhibitor of collagen deposition (L-azetidine-2-carboxylic acid); (2) a bacterial neutral protease (Dispase); and (3) synthetic fibronectin peptides that contained the arginine-glycine-asparate (RGD) sequence that is responsible for cell binding. Dispase and the RGD-containing peptides also inhibited cell implantation and prevented tumor formation in a surgical wound. We propose that inhibitors of attachment might be used either alone or with other biologic modifiers to prohibit implantation of free tumor cells at the time of surgery and thus, to prevent local tumor recurrence.