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Three-dimensional context regulation of metastasis

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Abstract

Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.

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Abbreviations

2D, 3D:

2- and 3-dimensional

Pa:

Pascals

ECM:

Extracellular matrix

MMP:

Matrix metalloproteinase

LOX:

Lysyl oxidase

HIF:

Hypoxia-inducible factor

CAF:

Cancer-associated fibroblast

TAM:

Tumor-associated macrophage

TGF:

Tissue growth factor

BMDC:

Bone marrow-derived cell

MEC:

Mammary epithelial cell

HMEC:

Human mammary epithelial cell

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Acknowledgements

We apologize to those authors whose excellent work could not be cited due to space limitations. This work was supported by DOD BCRP W81XWH-05-1-330, NCI CA078731, and DOE A107165 (VMW); and by The Institute of Cancer Research, and Cancer Research UK (JTE).

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Erler, J.T., Weaver, V.M. Three-dimensional context regulation of metastasis. Clin Exp Metastasis 26, 35–49 (2009). https://doi.org/10.1007/s10585-008-9209-8

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