Universitätsmedizin Mannheim, University of Heidelberg, Centre for Biomedicine and Medical Technology Mannheim (CBTM), TRIDOMUS-Gebäude Haus C, Ludolf-Krehl-Str. 13-17, D-68167 Mannheim, Germany.
Semin Cancer Biol. 2012 Jun;22(3):174-86. doi: 10.1016/j.semcancer.2012.02.007. Epub 2012 Feb 21.
The ability of tumor cells to leave a primary tumor, to disseminate through the body, and to ultimately seed new secondary tumors is universally agreed to be the basis for metastasis formation. An accurate description of the cellular and molecular mechanisms that underlie this multistep process would greatly facilitate the rational development of therapies that effectively allow metastatic disease to be controlled and treated. A number of disparate and sometimes conflicting hypotheses and models have been suggested to explain various aspects of the process, and no single concept explains the mechanism of metastasis in its entirety or encompasses all observations and experimental findings. The exciting progress made in metastasis research in recent years has refined existing ideas, as well as giving rise to new ones. In this review we survey some of the main theories that currently exist in the field, and show that significant convergence is emerging, allowing a synthesis of several models to give a more comprehensive overview of the process of metastasis. As a result we postulate a stromal progression model of metastasis. In this model, progressive modification of the tumor microenvironment is equally as important as genetic and epigenetic changes in tumor cells during primary tumor progression. Mutual regulatory interactions between stroma and tumor cells modify the stemness of the cells that drive tumor growth, in a manner that involves epithelial-mesenchymal and mesenchymal-epithelial-like transitions. Similar interactions need to be recapitulated at secondary sites for metastases to grow. Early disseminating tumor cells can progress at the secondary site in parallel to the primary tumor, both in terms of genetic changes, as well as progressive development of a metastatic stroma. Although this model brings together many ideas in the field, there remain nevertheless a number of major open questions, underscoring the need for further research to fully understand metastasis, and thereby identify new and effective ways of treating metastatic disease.
肿瘤细胞离开原发性肿瘤、在体内扩散并最终播种新的继发性肿瘤的能力被普遍认为是转移形成的基础。准确描述细胞和分子机制，将极大地促进合理开发治疗方法，有效地控制和治疗转移性疾病。已经提出了许多不同的、有时甚至相互矛盾的假说和模型来解释这个多步骤过程的各个方面，而且没有一个单一的概念能够完整地解释转移的机制，或者涵盖所有的观察和实验结果。近年来，转移研究取得了令人兴奋的进展，不仅完善了现有观点，还提出了新的观点。在这篇综述中，我们调查了目前该领域存在的一些主要理论，并表明出现了显著的趋同，使几个模型的综合能够更全面地概述转移过程。因此，我们提出了转移的基质进展模型。在这个模型中，肿瘤微环境的渐进性改变与原发性肿瘤进展过程中肿瘤细胞的遗传和表观遗传改变同样重要。基质和肿瘤细胞之间的相互调节相互作用改变了驱动肿瘤生长的细胞的干性，这种方式涉及上皮-间充质和间充质-上皮样转化。转移需要在继发性部位重新复制类似的相互作用才能生长。早期播散的肿瘤细胞可以在继发性部位与原发性肿瘤平行进展，包括遗传变化以及转移性基质的渐进性发展。虽然这个模型汇集了该领域的许多观点，但仍然存在一些重大的未解决问题，突出了进一步研究的必要性，以充分理解转移，并确定治疗转移性疾病的新方法。
