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