title: The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Cassie J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: 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.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Berg
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Birch
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Ennis
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cloix
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sumpton
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Kirsteen
authors.initials: K
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bridgeman
authors.affiliation: 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.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Vermeulen
authors.affiliation: 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.
authors.forename: Shane
authors.initials: S
authors.lastname: Foo
authors.affiliation: 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.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Kostaras
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: J Louise
authors.initials: JL
authors.lastname: Jones
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Haywood
authors.affiliation: School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
authors.forename: Ellie
authors.initials: E
authors.lastname: Pulleine
authors.affiliation: School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
authors.forename: Huabing
authors.initials: H
authors.lastname: Yin
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Strathdee
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: McNeish
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Zanivan
authors.affiliation: 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.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: j.norman@beatson.gla.ac.uk.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D012358:RNA, Transfer, Met / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology
chemical_list: D024043:Collagen Type II; D012358:RNA, Transfer, Met
keywords: cell migration; extracellular matrix; initiator methionine tRNA (tRNA(i)(Met)); secretome; tRNA repertoire; tumor angiogenesis; tumor stroma