Fidler I J
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Cancer Chemother Pharmacol. 1999;43 Suppl:S3-10. doi: 10.1007/s002800051091.
The major cause of death from cancer is metastases that are resistant to conventional therapies. Several reasons account for treatment failure in patients with metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects a small subpopulation of cells that preexist within a parental neoplasm. Although metastases can have a clonal origin, genetic instability results in rapid biological diversification and the regeneration of heterogeneous subpopulations of cells. Third, and perhaps the most important principle for the design of new cancer therapies, is that the outcome of metastasis depends on multiple interactions ("cross-talk") of metastatic cells with homeostatic mechanisms which the tumor cells usurp. The organ microenvironment can influence the biology of cancer growth, angiogenesis, and metastasis in several different ways. For example, the survival and growth of tumor cells are dependent on angiogenesis, which is mediated by an imbalance between positive and negative regulating molecules released by tumor cells, normal cells surrounding a tumor, and infiltrating lymphoid cells. Many cytokines that stimulate or inhibit angiogenesis are present in different tissues, and thus the organ environment profoundly influences this process. Moreover, the organ microenvironment can also influence the response of metastases to chemotherapy by regulating the expression of different drug resistance genes, such as mdr-1. The finding that the resistance of metastases to some chemotherapeutic agents can be mediated by epigenetic mechanisms has obvious implications for therapy. The identification of organ-specific cytokines that can upregulate expression of mdr-1 (or other resistant mechanisms) may suggest an approach to overcome the resistance of some metastases to particular chemotherapeutic agents. Therefore therapy of metastasis should be targeted not only against metastatic tumor cells, but also the homeostatic factors that are favorable to metastasis, growth, and survival of the metastatic cells.
癌症致死的主要原因是对传统疗法产生抗性的转移灶。转移癌患者治疗失败有多种原因。首先，肿瘤在生物学上具有异质性，包含具有不同血管生成、侵袭和转移特性的细胞亚群。其次，转移过程会挑选出亲代肿瘤中预先存在的一小部分细胞亚群。虽然转移灶可能起源于克隆，但基因不稳定性会导致快速的生物学多样化以及异质性细胞亚群的再生。第三，也许也是设计新型癌症疗法最重要的原则，即转移的结果取决于转移细胞与肿瘤细胞所篡夺的稳态机制之间的多种相互作用（“串扰”）。器官微环境可通过几种不同方式影响癌症生长、血管生成和转移的生物学特性。例如，肿瘤细胞的存活和生长依赖于血管生成，这是由肿瘤细胞、肿瘤周围正常细胞以及浸润淋巴细胞释放的正负调节分子之间的失衡介导的。许多刺激或抑制血管生成的细胞因子存在于不同组织中，因此器官环境会深刻影响这一过程。此外，器官微环境还可通过调节不同耐药基因（如mdr - 1）的表达来影响转移灶对化疗的反应。转移灶对某些化疗药物的抗性可由表观遗传机制介导这一发现对治疗具有明显的启示意义。鉴定能够上调mdr - 1（或其他抗性机制）表达的器官特异性细胞因子，可能提示一种克服某些转移灶对特定化疗药物抗性的方法。因此，转移癌的治疗不仅应针对转移性肿瘤细胞，还应针对有利于转移细胞转移、生长和存活的稳态因子。
