Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Metastasis Rev. 2012 Dec;31(3-4):479-91. doi: 10.1007/s10555-012-9380-x.
Paget's "seed and soil" hypothesis stated that cancer metastasis requires permissive interactions between tumor cells and secondary organ microenvironments. Many of these "permissive interactions" are now known to be growth factor receptor and ligand interactions by which metastatic tumor cells coopt signaling pathways normally used by host organs. However, although cancer cell signaling pathways responsible for primary cancer growth have been extensively characterized, signaling pathways important in supporting tumor cell-secondary organ heterotypic interactions have been neglected. Even as targeted therapies have shown promise and efficacy in treating myriad primary tumors, metastatic cancer remains incurable. Here, we will discuss several growth factor signaling pathways known to be involved in both general and site-specific metastasis. We will address the complexity in generalizing the role of growth factor signaling in metastasis, as both pro- and antimetastatic roles for the same pathways have been demonstrated depending upon context. We will discuss the limitations of current usage of targeted therapies to pathways known to be dysregulated in metastasis. We propose that the future of cancer metastasis-targeted therapy will lie in better understanding of the interactions between tumor cells and the secondary organ microenvironments that may guide rationally designed personalized combinatorial targeted regimens. We hope to promote research to better understand the complex process of metastasis and ultimately better treatments for the abjectly underserved population of patients with metastatic cancer.
佩吉特的“种子和土壤”假说指出，癌症转移需要肿瘤细胞与次级器官微环境之间的许可性相互作用。现在已知，这些“许可性相互作用”中的许多是生长因子受体和配体相互作用，通过这种作用，转移性肿瘤细胞会篡夺宿主器官正常使用的信号通路。然而，尽管负责原发性癌症生长的癌细胞信号通路已被广泛研究，但对于支持肿瘤细胞与次级器官异型相互作用的信号通路却被忽视了。尽管靶向治疗在治疗多种原发性肿瘤方面显示出了希望和疗效，但转移性癌症仍然无法治愈。在这里，我们将讨论几种已知参与一般和特定部位转移的生长因子信号通路。我们将讨论在一般化生长因子信号在转移中的作用时所面临的复杂性，因为同一途径的促转移和抗转移作用已经根据具体情况得到了证明。我们将讨论当前针对已知在转移中失调的途径的靶向治疗的局限性。我们提出，癌症转移靶向治疗的未来在于更好地理解肿瘤细胞与可能指导合理设计个性化联合靶向治疗方案的次级器官微环境之间的相互作用。我们希望促进对转移这一复杂过程的研究，最终为转移性癌症患者这一严重服务不足的人群提供更好的治疗方法。
