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      The metastatic niche and stromal progression

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          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.

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          Most cited references61

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Integrin-regulated FAK-Src signaling in normal and cancer cells.

            Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.
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              The metastatic niche: adapting the foreign soil.

              The 'seed and soil' hypothesis for metastasis sets forth the concept that a conducive microenvironment, or niche, is required for disseminating tumour cells to engraft distant sites. This Opinion presents emerging data that support this concept and outlines the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour. To enable improvements in the prognosis of advanced malignancy, early interventions that target both the disseminating seed and the metastatic soil are likely to be required.
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                Author and article information

                Contributors
                +49-621-3839955 , +49-621-3839961 , Sleeman@medma.uni-heidelberg.de
                Journal
                Cancer Metastasis Rev
                Cancer Metastasis Rev
                Cancer Metastasis Reviews
                Springer US (Boston )
                0167-7659
                1573-7233
                15 June 2012
                15 June 2012
                December 2012
                : 31
                : 3-4
                : 429-440
                Affiliations
                [1 ]Centre for Biomedicine and Medical Technology Mannheim (CBTM), Universitätsmedizin Mannheim, University of Heidelberg, TRIDOMUS-Gebäude Haus C, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, Germany
                [2 ]KIT Karlsruhe Campus Nord, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
                Article
                9373
                10.1007/s10555-012-9373-9
                3470821
                22699312
                d351debd-ef98-4ad8-9522-d9c270714d8b
                © The Author(s) 2012
                History
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media New York 2012

                Oncology & Radiotherapy
                metastatic niche,pre-metastatic niche,microenvironment,stromal progression,metastasis,dormancy

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