Abstract
The tumor stroma is comprised of extracellular matrix, non-malignant cells, and the signaling molecules they produce. It is an integral and vital component of primary tumors that together with the underlying genetic defects in the tumor cells determines the growth characteristics, morphology, and invasiveness of the tumor. In parallel to continuing genetic changes in the tumor cells themselves, the tumor stroma progressively evolves during primary tumor development. Cancer cells that disseminate from primary tumors are dependent on this stromal microenvironment, and therefore the microenvironment they encounter at secondary sites determines their fate. For those cells that survive at these sites, stromal progression can serve to re-establish a supportive tumor stroma, fostering the outgrowth of the cells as metastases. Formation of a metastatic niche that supports the survival and growth of disseminated tumor cells is a key feature of this stromal progression. The endogenous organ microenvironment can provide components of the metastatic niche. In addition, microenvironmental changes in organs prior to receipt of disseminated tumor cells can be induced by factors secreted systemically by primary tumors, causing the formation of pre-metastatic niches. Further maturation of metastatic niches can be responsible for the re-activation of dormant disseminated tumor cells many years after removal of the primary tumor. The concept of the metastatic niche and stromal progression has profound consequences for our understanding of metastatic disease, and promises to open up new strategies for the diagnosis, prognostic evaluation, and therapy of cancer.
Highlights
After invading out of the primary tumor and entering the vasculature, tumor cells can in principle be transported throughout the body
A key step in the formation of metastases is the exit of these circulating tumor cells (CTCs) from the circulatory system and their entry into secondary sites to become disseminated tumor cells (DTCs)
Hypoxia promotes the formation of an inflammatory milieu [38], which supports metastatic outgrowth, and which is likely to an important end point of metastatic niche formation
Summary
After invading out of the primary tumor and entering the vasculature, tumor cells can in principle be transported throughout the body. Metastatic niches can be derived from the foundation of particular microenvironments found endogenously in organs where metastases form Their formation can be remotely induced at least in part by primary tumors before the arrival and establishment of DTCs (termed pre-metastatic niches). The development and evolution of metastatic niches should be seen in the broader context of tumorigenesis and Cancer Metastasis Rev tumor progression as a whole, as suggested by the stromal progression model of metastasis [3]. In this model, the formation of primary tumors is dependent on progressive genetic changes in cancer cells and on the progressive development of an inflammatory tumor stroma. I survey what we currently know about the form, regulation and function of metastatic niches, and discuss some of the potential clinical implications of their existence
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