Clinical & Experimental Metastasis

, Volume 26, Issue 1, pp 35–49 | Cite as

Three-dimensional context regulation of metastasis

  • Janine T. ErlerEmail author
  • Valerie M. WeaverEmail author


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.


Collagen cross-linking Hypoxia Matrix remodeling Matrix stiffness Metastasis Tumor progression 


2D, 3D

2- and 3-dimensional




Extracellular matrix


Matrix metalloproteinase


Lysyl oxidase


Hypoxia-inducible factor


Cancer-associated fibroblast


Tumor-associated macrophage


Tissue growth factor


Bone marrow-derived cell


Mammary epithelial cell


Human mammary epithelial cell



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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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  1. 1.Hypoxia and Metastasis Team, Section of Cell and Molecular BiologyThe Institute of Cancer ResearchLondonUK
  2. 2.Departments of Surgery, Anatomy, Bioengineering and Therapeutic Sciences, Center for Bioengineering and Tissue Regeneration and Institute for Regenerative MedicineUniversity of California San FranciscoSan FranciscoUSA

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