The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis

Clarke, C. J. et al. (2016) The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Current Biology, 26(6), pp. 755-765. (doi:10.1016/j.cub.2016.01.045) (PMID:26948875) (PMCID:PMC4819511)

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Abstract

Summary: Expression of the initiator methionine tRNA (tRNAi Met) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi Met expression levels influence tumor progression. We have found that tRNAi Met expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi Met in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi Met contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi Met gene (2+tRNAi Met mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi Met mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi Met mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi Met significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi Metoverexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl- 3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi Met-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi Met mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi Met levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis.

Item Type:Articles
Additional Information:Supported by funding from Cancer Research UK— grant numbers C596/A17196 (core), C596/A12935 (to S.Z.), and C596/A18277 (to J.N.). A.R.R., S.F., E.K., and V.L.B. were supported by funding from Breakthrough Breast Cancer.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Yin, Professor Huabing and Pulleine, Miss Ellie and Campbell, Mr Andrew and Zanivan, Dr Sara Rossana and Strathdee, Dr Douglas and Blyth, Dr Karen and Ennis, Dr Darren and Sumpton, Mr David and Cloix, Dr Catherine and Birch, Dr Joanna and Mitchell, Mrs Louise and Nixon, Mr Colin and Campbell, Dr Kirsteen and Clarke, Dr Cassie and Mcneish, Professor Iain and Berg, Dr Tracy and Sansom, Professor Owen
Authors: Clarke, C. J., Berg, T. J., Birch, J., Ennis, D., Mitchell, L., Cloix, C., Campbell, A., Sumpton, D., Nixon, C., Campbell, K., Bridgeman, V. L., Vermeulen, P. B., Foo, S., Kostaras, E., Jones, J. L., Haywood, L., Pulleine, E., Yin, H., Strathdee, D., Sansom, O., Blyth, K., Mcneish, I., Zanivan, S., Reynolds, A. R., and Norman, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Current Biology
Publisher:Elsevier
ISSN:0960-9822
ISSN (Online):1879-0445
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Current Biology 26(6): 755-765
Publisher Policy:Reproduced under a Creative Commons licence
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