Microenvironmental regulation of metastasis

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Abstract
The tumour microenvironment has a major role in modulating the metastatic capacity of most cancers. Seminal experiments indicated that certain microenvironments can suppress malignancy. However, in most tumours these restraints are overcome such that the tumour now exploits the supporting cells to increase metastatic potential. Primary and metastatic tumours cause systemic perturbations that often involve mobilizing bone marrow-derived cells that home to the tumour and promote tumour progression, malignant cell escape and survival, and growth at the secondary site. Primary tumours recruit macrophages to their microenvironment and these cells increase metastatic potential by increasing tumour cell migration, invasion and intravasation. They also increase angiogenesis and thereby increase the targets for metastatic cell escape. Myeloid cell-derived suppressor cells suppress immune responses to newly displayed tumour antigens and promote the metastatic potential of the tumour. Mesenchymal stem cells can differentiate into many different cell types and are recruited to primary tumours where they enhance metastasis. Tumour cells are protected in their travels through the circulation, particularly by platelets. These platelets together with the tumour cells activate the clotting system such that microthrombi form that help tumour cells lodge in target tissues. The formation of metastases has many rate-limiting steps including survival in the distant organ, extravasation and the establishment of persistent growth. Microenvironmental cues are important at all steps and the recruitment of a variety of bone marrow-derived cells including endothelial progenitors and myeloid cell-derived cells is crucial for these processes.