Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.
The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo. We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC.
Hypoxia and Metastasis Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK.
A-M
AM
Baker
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Bird
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Lang
T R
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Cox
J T
JT
Erler
D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010766:Phosphorylation; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054457:Tissue Scaffolds / Q000737:chemistry*
C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D051417:Focal Adhesion Kinase 1; D015688:Oncogene Protein pp60(v-src); C496050:PTK2 protein, human