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Curr Biol. 2016 Mar 21;26(6):755-65. doi: 10.1016/j.cub.2016.01.045. Epub 2016 Mar 3.

The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.

Author information

1
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London SW3 6JB, UK.
3
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
4
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London SW3 6JB, UK; Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Wilrijk 2610, Antwerp, Belgium.
5
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
6
School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
7
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: andrew.reynolds@icr.ac.uk.
8
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: j.norman@beatson.gla.ac.uk.

Abstract

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(Met)-overexpressing 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.

KEYWORDS:

cell migration; extracellular matrix; initiator methionine tRNA (tRNA(i)(Met)); secretome; tRNA repertoire; tumor angiogenesis; tumor stroma

PMID:
26948875
PMCID:
PMC4819511
DOI:
10.1016/j.cub.2016.01.045
[Indexed for MEDLINE]
Free PMC Article

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