The Metastatic Microenvironment

  • Shelly Maman
  • Isaac P. Witz


Metastasis is the major killer of cancer patients. Although increased understanding of the metastatic process was achieved in recent years, the mechanisms underlying the progression of cancer cells to form site-specific metastasis are still awaiting complete elucidation. The current consensus is that circulating tumor cells disseminate into future metastatic sites and that these disseminated tumor cells form micrometastasis in these sites. The micrometastases remain in a state of dormancy in these sites until “awakened” to progress towards overt metastases. Whereas the evidence implicating chemokine–chemokine receptor interactions as the mechanism responsible for the targeted migration of tumor cells to future metastatic sites is quite strong, the mechanisms that maintain dormancy of disseminated tumor cells and the mechanisms that awaken these dormant micrometastases, driving their progression towards frank metastasis, are still obscure. It is clear, however, that the metastatic microenvironment plays a major role in these events. Three topics are discussed in this review: Mechanisms that are involved in the targeted migration of tumor cells to future metastatic sites; Specific molecular signatures expressed by metastases and micrometastases and interactions between metastatic and micrometastatic cells with the metastatic microenvironment. In reviewing these topics we focused on studies performed in our lab with neuroblatoma lung and melanoma brain metastasis.


Tumor Metastatic microenvironment Metastasis Site-specific metastasis Micrometastasis Dormancy Chemokines Neuroblastoma Melanoma Molecular signature 



Tumor microenvironment


cancer-associated fibroblast


chemokine (C-X-C motif) ligand


Stromal cell-derived actor


Chemokine (C–C motif) ligand


Tumor necrosis factor


Monocyte chemotactic protein


Chemokine (C-X-C motif) receptor




Transendothelial migration


Chemokine (C–C) motif receptor


Circulating tumor cells


Disseminated tumor cells


Paired-like homeobox


Matrix metalloproteinase


Extracellular Signal-Regulated Kinase


Polymerase chain reaction



The studies performed in Dr. Witz’s laboratory are generously supported by the following foundations and individuals: The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Needham, MA, USA); Bonnie and Steven Stern (New York, NY, USA); The Deutsche Forschungsgemeinschaft (DFG); The Fred August and Adele Wolpers Charitable Fund (Clifton, NJ, USA); the late Natan Blutinger (West Orange, NJ, USA); The Pikovsky Fund (Jerusalem, Israel); and James J. Leibman and Rita S. Leibman Endowment Fund for Cancer Research (New York, NY, USA).


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Cell Research and Immunology George S. Wise Faculty of Life SciencesTel Aviv UniversityTel Aviv Israel
  2. 2.Institute of Human VirologyUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of Cell Research and Immunology George SWise Faculty of Life Sciences, Tel Aviv UniversityTel AvivIsrael

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