Thomas R. Cox, Jan 2013

Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis

Our recent work on the role of Lysyl Oxidase in stimulating tumour angiogenesis in colorectal cancer has just been published in Cancer Research.

Image: Immunohistochemistry for LOX expression (shown in brown) in a patient colorectal cancer sample

In this paper we show that the cancer secreted enzyme Lysyl Oxidase (LOX) plays a critical role in stimulating angiogenesis in the growth of colorectal cancers. We show that the expression of LOX in colorectal cancers is correlated with the number of blood vessels in the tumours of colorectal cancer patients. Our experiments provide evidence that LOX expression can drive VEGF secretion through a mechanism involving PDGFRβ-mediated activation of Akt. As such, our results suggest that inhibition of LOX in a therapeutic setting has potential to slow cancer progression not only by inhibiting invasion and metastasis but also by reducing tumour angiogenesis. These findings have important clinical implications for the development of novel strategies for the treatment of patients with cancer.

Abstract

Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types.

Links

View article on Cancer Research homepage
View abstract on PubMed

Citation

Baker AM, Bird D, Welti J, Gourlaouen M, Lang G, Murray G, Reynolds AR, Cox TR, Erler JT. Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis
Cancer Research; Jan 15;73(2):583-94 (2013) | doi: 10.1158/0008-5472.CAN-12-2447

Funding

Funding was provided by the Medical Research Council, the Institute of Cancer Research, Cancer Research UK and Breakthrough Breast Cancer. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. The development of the CRC TMA was supported by funding from the Scottish Academic Health Sciences Collaboration, which is supported by the Chief Scientist Office of the Scottish Government Health Department.