Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture.
Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture.
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作者：
I. Fidler
转移的过程不是随机的。相反，它由一系列相连的、连续的步骤组成，如果要发生转移，肿瘤细胞必须完成这些步骤。虽然这个过程中的一些步骤包含随机因素，但总的来说，转移有利于在母体肿瘤中预先存在的少数细胞亚群的生存和生长。此外，转移可以有克隆起源，不同的转移可以起源于单个细胞的增殖。转移的结果取决于转移细胞与不同器官环境的相互作用。器官特异性转移已在多种实验肿瘤系统中得到证实。此外，我们已经发现肿瘤生长是特定于一个器官内的特定部位。人类癌症是否也能得出同样的结论直到最近才得到解答。我们和其他实验室的研究表明，将手术标本中提取的人类癌细胞植入裸鼠的正确解剖部位可以提供一种合适的人类肿瘤转移模型。人类肾癌、结肠癌和黑色素瘤的克隆分析显示，这些肿瘤的转移性质确实是异质性的，这是在原位植入后才观察到的。因此，特定器官在环境中的生长可以是选择性的，环境本身影响这一过程。虽然血管和局部免疫可以促进或延缓肿瘤的生长是很清楚的，但我们集中精力了解器官损伤和随后的修复过程是如何促进肿瘤细胞增殖的。在去肝裸鼠中发现人结肠癌细胞生长加速，而在去肾裸鼠中发现人肾癌细胞生长加速。这些数据表明，肿瘤细胞可能通过与正常细胞相似的机制来识别系统生理信号。综上所述，调控转移的关键因素是转移细胞的内在特性和参与稳态的宿主因子。最近我们对转移的理解的增加应该为开发更有效的治疗播散性癌症的方法提供重要的线索。
The process of metastasis is not random. Rather, it consists of a series of linked, sequential steps that must be completed by tumor cells if a metastasis is to develop. Although some of the steps in this process contain stochastic elements, as a whole, metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Moreover, metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with different organ environments. Organ-specific metastases have been demonstrated in a variety of experimental tumor systems. Moreover, we have found tumor growth that is specific to a particular site within one organ. Whether the same conclusions can be reached for human cancers remained unanswered until very recently. Studies from our laboratory and from others have shown that the implantation of human cancer cells derived from surgical specimens into correct anatomical sites of nude mice can provide a suitable model of metastasis of human tumors. Clonal analysis of a human renal carcinoma, colon carcinomas, and melanomas has revealed that these tumors are indeed heterogeneous for metastatic properties, an observation made only after orthotopic implantation. Thus, growth in the environment of specific organs can be selective and the environment per se influences this process. While it is clear that vascularity and local immunity can facilitate or retard tumor growth, we have concentrated on understanding how damage to an organ and the subsequent repair process can facilitate tumor cell proliferation. Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be recognized by neoplastic cells presumably by mechanisms similar to those shared by their normal cell counterparts. In summary, the critical factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis. The recent increase in our understanding of metastasis should provide important leads for developing more effective approaches to the treatment of disseminated cancer.