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Review
. 2009;26(1):35-49.
doi: 10.1007/s10585-008-9209-8. Epub 2008 Sep 24.

Three-dimensional context regulation of metastasis

Janine T Erler  1 , Valerie M Weaver
Affiliations
Review

Three-dimensional context regulation of metastasis

Janine T Erler et al. Clin Exp Metastasis. 2009.

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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Figures

Fig. 1
Fig. 1
Mammary epithelial growth and morphogenesis is regulated by matrix stiffness. (a) 3D cultures of normal mammary epithelial cells (MECs) within collagen gels of different concentration. Stiffening the ECM through an incremental increase in collagen concentration (soft gels: 1 mg/ml Collagen I, 140 Pa; stiff gels 3.6 mg/ml Collagen I, 1,200 Pa) results in the progressive perturbation of morphogenesis, and the increased growth and modulated survival of MECs. Altered mammary acini morphology is illustrated by the destabilization of cell–cell adherens junctions and disruption of basal tissue polarity indicated by the gradual loss of cell–cell localized β-catenin (green) and disorganized β4 integrin (red) visualized through immunofluorescence and confocal imaging. (b) Confocal immunofluorescence images of MEC colonies on soft and stiff gels (140 vs. >5,000 Pa) stained for β-catenin (red) and E-cadherin (green), and counterstained with DAPI (blue) after triton X-100 extraction. β-catenin could be extracted from the sites of cellcell interaction in MEC colonies formed on a stiff but not on a soft gel, indicating that adherens junctions are less stable in MEC structures formed on stiff gels. White arrows indicate diffuse staining patterns of β-catenin and E-cadherin (Modified from Kass et al. [18])
Fig. 2
Fig. 2
Schematic to demonstrate the interplay between hypoxia and matrix remodeling, using lysyl oxidase (LOX) as an example. LOX expression is increased in pre-malignant tissue, where it cross-links collagens in the ECM increasing matrix stiffness and enabling ECM remodeling. This allows for malignant transformation and primary tumor growth. As the tumor grows larger, regions become subjected to hypoxic conditions. In response to hypoxia, tumor cells increase expression of proteins involved in collagen biosynthesis and processing, including LOX. This results in increased matrix deposition, collagen cross-linking, matrix remodeling and matrix stiffness, which in turn encourage a hypoxic environment. LOX secreted by hypoxic tumor cells is additionally involved in the formation of a pre-metastatic niche at distant sites of future metastasis. Increased collagen cross-linking and matrix remodeling attract bone marrow-derived cells to the site, which create a niche permissive for metastatic tumor cell attachment and growth. Again, subsequent matrix remodeling and increased stiffness at these metastatic sites would enhance hypoxia, which in turn elevates expression of proteins involved in collagen biosynthesis and processing, further increasing matrix remodeling and matrix stiffness. This feed forward mechanism is further enhanced by matrix metalloproteinase (MMP) activity. MMP expression and activity is elevated by both increased matrix stiffness and by hypoxia. Thus, the symbiotic interaction between ECM remodeling and hypoxia, two non-cellular components of the tissue microenvironment, can cooperatively drive tumor metastasis by influencing common targets
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