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The Metastatic Microenvironment

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The Tumor Immunoenvironment

Abstract

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.

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Abbreviations

TME:

Tumor microenvironment

CAF:

cancer-associated fibroblast

CXCL:

chemokine (C-X-C motif) ligand

SDF:

Stromal cell-derived actor

CCL:

Chemokine (C–C motif) ligand

TNF:

Tumor necrosis factor

MCP:

Monocyte chemotactic protein

CXCR:

Chemokine (C-X-C motif) receptor

IFN:

Interferon

TEM:

Transendothelial migration

CCR:

Chemokine (C–C) motif receptor

CTC:

Circulating tumor cells

DTC:

Disseminated tumor cells

PHOX:

Paired-like homeobox

MMP:

Matrix metalloproteinase

ERK:

Extracellular Signal-Regulated Kinase

PCR:

Polymerase chain reaction

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Acknowledgments

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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Authors and Affiliations

  1. Department of Cell Research and Immunology George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Shelly Maman & Isaac P. Witz

  2. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA

    Shelly Maman & Isaac P. Witz

  3. Department of Cell Research and Immunology George S, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel

    Isaac P. Witz

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  1. Shelly Maman
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Correspondence to Isaac P. Witz .

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Editors and Affiliations

  1. Department of Pathology, University of Pittsburgh Medical Center, 3550 Terrace Street Scaife Hal, Pittsburgh, 15213, Pennsylvania, USA

    Michael R. Shurin

  2. , Clinical Cooperation Unit Dermato-Oncolo, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Viktor Umansky

  3. , SAIC-Frederick, Inc., National Cancer Institute at Frederick, Post Office B, Frederick, 21702, Maryland, USA

    Anatoli Malyguine

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Maman, S., Witz, I.P. (2013). The Metastatic Microenvironment . In: Shurin, M., Umansky, V., Malyguine, A. (eds) The Tumor Immunoenvironment. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6217-6_2

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