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Review
. 2013 Apr;91(4):411-29.
doi: 10.1007/s00109-013-1021-5. Epub 2013 Mar 21.

The metastasis-promoting roles of tumor-associated immune cells

Affiliations
Review

The metastasis-promoting roles of tumor-associated immune cells

Heath A Smith et al. J Mol Med (Berl). 2013 Apr.

Abstract

Tumor metastasis is driven not only by the accumulation of intrinsic alterations in malignant cells, but also by the interactions of cancer cells with various stromal cell components of the tumor microenvironment. In particular, inflammation and infiltration of the tumor tissue by host immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, have been shown to support tumor growth in addition to invasion and metastasis. Each step of tumor development, from initiation through metastatic spread, is promoted by communication between tumor and immune cells via the secretion of cytokines, growth factors, and proteases that remodel the tumor microenvironment. Invasion and metastasis require neovascularization, breakdown of the basement membrane, and remodeling of the extracellular matrix for tumor cell invasion and extravasation into the blood and lymphatic vessels. The subsequent dissemination of tumor cells to distant organ sites necessitates a treacherous journey through the vasculature, which is fostered by close association with platelets and macrophages. Additionally, the establishment of the pre-metastatic niche and specific metastasis organ tropism is fostered by neutrophils and bone marrow-derived hematopoietic immune progenitor cells and other inflammatory cytokines derived from tumor and immune cells, which alter the local environment of the tissue to promote adhesion of circulating tumor cells. This review focuses on the interactions between tumor cells and immune cells recruited to the tumor microenvironment and examines the factors allowing these cells to promote each stage of metastasis.

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Conflict of interest statement

Disclosure

The authors declare that they have no conflict of interests.

Figures

Figure 1
Figure 1. Recruitment of tumor-promoting immune cells contributes to each stage of tumor progression and metastasis
A) Neoplasia: Genetic mutations arising from radiation, carcinogen exposure, or chronic infection initiates neoplastic growth and the initial inflammatory immune state. B) Inflammation: A recurring cycle of chronic inflammation, immune cell recruitment, and secretion of tumor promoting cytokines (green) promotes immunosuppression and tumor proliferation. Chemokines secreted from tumor cells and immune cells in the inflammatory tumor microenvironment that recruit tumor-promoting immune cell populations are listed below the depicted bone marrow compartment. C) EMT: Cytokines and factors produced by immune cells contribute to the initiation of an epithelial conversion to a mesenchymal state with concurrent induction of mesenchymal and reduction in epithelial proteins, respectively (blue). D) Invasion: Immune cells recruited to the tumor tissue secrete proteases (Red) and upregulate tumor-intrinsic factors that promote invasion through the basement membrane and surrounding ECM into the vasculature. E) Intravasation: Immune cells mediate prostaglandin and epiregulin expression to facilitate vascular permeability and migration into the circulation. F) Circulation: Platelets, neutrophils, lymphocytes, and inflammatory chemokines direct CTC travel and protect tumor cells from shear stress and immune-mediated recognition and lysis. G) Extravasation: cytokines secreted from immune cells and the inflammatory tumor microenvironment and direct contact with neutrophils increase expression of adhesion proteins such as ANGPTL4, ICAM-1, VCAM-1, and fibronectin on endothelial cells, which facilitates CTC vascular arrest and extravasation at the metastatic site. H) Colonization: BMDCs and myeloid cells help to establish the pre-metastatic niche by upregulating adhesion molecules, while platelets and neutrophils can also mediate CTC arrest and adhesion to tissue-specific endothelial cells. Green = cytokines/chemokines; Red = proteases; Blue = other metastasis related proteins (e.g. transcription factors and adhesion molecules).

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