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The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines

  • Review Paper
  • Published:
Cancer Microenvironment

Abstract

Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines and of the inflammatory cytokine tumor necrosis factor α (TNFα) in determining cell motility processes that eventually have profound effects on tumor growth and metastasis. First, the effects of inflammatory chemokines such as CCL2 (MCP-1), CCL5 (RANTES) and CXCL8 (IL-8) are described, regulating the inward flow of leukocyte sub-populations with pro-tumoral activities, such as tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), Th17 cells and Tregs. Then, the ability of inflammatory chemokines to induce endothelial cell migration, sprouting and tube formation is discussed, with its implications on tumor angiogenesis. This part is followed by an in depth description of the manners by which TNFα potentiates the above activities of the inflammatory chemokines, alongside with its ability to directly induce migratory processes in the tumor cells thus promoting metastasis. Note worthy is the ability of TNFα to induce in the tumor cells the important process of epithelial-to-mesenchymal transition (EMT). Emphasis is given to the ability of TNFα to establish an inflammatory network with the chemokines, and in parallel to form a cell re-modeling network together with transforming growth factor β (TGFβ). The review concludes by discussing the implications of such networks on disease course, and on the future design of therapeutic measures in cancer.

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Abbreviations

CAF:

Cancer-Associated Fibroblasts

DCIS:

Ductal Carcinoma In Situ

EMT:

Epithelial-to-Mesenchymal Transition

IDC:

Invasive Ductal Carcinoma

IFNγ:

Interferon γ

IL-1β:

Interleukin 1β

IMPC:

Invasive Micropapillary Carcinoma

MDSC:

Myeloid-Derived Suppressor Cells

MMP:

Matrix Metalloproteinases

MSC:

Mesenchymal Stem Cells

TAM:

Tumor-Associated Macrophages

TAN:

Tumor-Associated Neutrophils

TGFβ:

Transforming Growth Factor β

TNFα:

Tumor Necrosis Factor α

VEGF:

Vascular Endothelial Growth Factor

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Acknowledgments

The author thanks Israel Science Foundation, Israel Ministry of Health and Federico Foundation for supporting the studies related to this review, which were performed in her laboratory. The author also thanks the members of her laboratory for their contribution to studies on inflammation in cancer.

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

    Adit Ben-Baruch

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Ben-Baruch, A. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines. Cancer Microenvironment 5, 151–164 (2012). https://doi.org/10.1007/s12307-011-0094-3

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  • DOI: https://doi.org/10.1007/s12307-011-0094-3

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