LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis
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LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. / Cox, Thomas R; Bird, Demelza; Baker, Ann-Marie; Barker, Holly E; Ho, Melisa W-Y; Lang, Georgina; Erler, Janine T.
In: Cancer Research, Vol. 73, No. 6, 15.03.2013, p. 1721-32.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis
AU - Cox, Thomas R
AU - Bird, Demelza
AU - Baker, Ann-Marie
AU - Barker, Holly E
AU - Ho, Melisa W-Y
AU - Lang, Georgina
AU - Erler, Janine T
PY - 2013/3/15
Y1 - 2013/3/15
N2 - Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer.
AB - Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer.
U2 - 10.1158/0008-5472.CAN-12-2233
DO - 10.1158/0008-5472.CAN-12-2233
M3 - Journal article
C2 - 23345161
VL - 73
SP - 1721
EP - 1732
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 6
ER -
ID: 45826172