Greig R G, Trainer D L
Cancer Metastasis Rev. 1986;5(1):3-14. doi: 10.1007/BF00049527.
The eradication of established metastases in patients with malignant tumors is the single most important objective in clinical oncology. The current panel of antineoplastic agents discovered through random and semiempirical screening procedures has proven largely ineffective in treating disseminated disease and there is a clear and urgent need for more efficient antimetastatic drugs. Unfortunately, although progress has been made in examining the biology of metastatic spread, our understanding of the pharmacology, biochemistry and molecular genetics of this process is meager and insufficient to provide a rational foundation for the design of mechanism-based antineoplastic agents. Faced on the one hand with the failure of existing drugs to control metastatic spread and on the other with a dearth of alternative pharmacological approaches, the prospect of offering significantly improved therapy to the cancer patient of the 1990's is poor. The challenge of the coming decade lies in obtaining better insights into the molecular mechanisms of metastasis and using this information to identify pharmacological opportunities to curtail the proliferation of secondary tumor growths. As a first step toward this goal we need to define more rigorously what constitutes a therapeutic target in malignant disease and what steps in the pathogenesis of cancer metastasis represent the gravest risk to the patient and thus are most eligible for direct pharmacological intervention. In addressing these issues and developing future strategies for antimetastatic drugs, Paget's 100 year-old 'seed and soil' hypothesis continues to offer a useful conceptual framework for analysis of metastatic behavior. Although Paget's proposal has been validated by a century of clinical observation, efforts to define the 'seed and soil' theory in molecular terms have not been attempted. With the advent of more efficient methodologies for culturing human normal and neoplastic cells coupled with the availability of microanalytical technologies it now becomes possible to investigate and identify the complementary biochemical components of the tumor cell 'seed' and organ 'soil' that combine to encourage the proliferation of metastases. With this information the design of specific pharmacological strategies to uncouple the 'seed and soil' relationship may emerge as a potential therapeutic approach for antagonizing the growth of disseminated malignant tumors.
根除恶性肿瘤患者体内已形成的转移灶是临床肿瘤学中最重要的单一目标。目前通过随机和半经验筛选程序发现的抗肿瘤药物在治疗播散性疾病方面已被证明大多无效，因此迫切需要更有效的抗转移药物。不幸的是，尽管在研究转移扩散的生物学方面取得了进展，但我们对这一过程的药理学、生物化学和分子遗传学的理解仍然匮乏，不足以提供设计基于机制的抗肿瘤药物的合理依据。一方面面临现有药物无法控制转移扩散的问题，另一方面缺乏替代药理学方法，为20世纪90年代的癌症患者提供显著改善治疗的前景不佳。未来十年的挑战在于更深入地了解转移的分子机制，并利用这些信息确定减少继发性肿瘤生长增殖的药理学机会。作为实现这一目标的第一步，我们需要更严格地定义什么构成恶性疾病的治疗靶点，以及癌症转移发病机制中的哪些步骤对患者构成最严重的风险，因此最适合直接进行药理学干预。在解决这些问题并制定未来抗转移药物策略时，佩吉特提出的已有百年历史的“种子与土壤”假说仍然为分析转移行为提供了一个有用的概念框架。尽管佩吉特的提议已通过一个世纪的临床观察得到验证，但尚未有人尝试从分子层面定义“种子与土壤”理论。随着培养人类正常细胞和肿瘤细胞的更有效方法的出现，以及微分析技术的可用性，现在有可能研究和识别肿瘤细胞“种子”和器官“土壤”中相互补充的生化成分，这些成分共同促进转移灶的增殖。有了这些信息，设计特定的药理学策略来解除“种子与土壤”关系可能会成为对抗播散性恶性肿瘤生长的一种潜在治疗方法。
