Abstract
SummaryExpression of the initiator methionine tRNA (tRNAiMet) is deregulated in cancer. Despite this fact, it is not currently known how tRNAiMet expression levels influence tumor progression. We have found that tRNAiMet expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAiMet in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAiMet contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAiMet gene (2+tRNAiMet mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAiMet mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAiMet mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAiMet significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAiMet-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 tRNAiMet-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+tRNAiMet 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 tRNAiMet 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.
Highlights
The use of transcriptomics and proteomics to understand cellular function has been pivotal in advancing our knowledge of the molecular basis of disease processes, and the combined use of these approaches is beginning to highlight discord between the control of gene expression at the levels of transcription and translation
Increased Expression of tRNAiMet in the Host Animal Promotes Tumor Growth and Angiogenesis To determine whether tRNA expression is altered in the tumor stroma, we measured tRNA levels in immortalized human mammary carcinoma-associated fibroblasts and compared these with immortalized matched normal fibroblast controls. iCAFs were generated by co-injecting iNFs with Ras-transformed MCF7 cells subcutaneously into mice [11]
These iCAFs are established to have an enhanced capacity to promote tumor growth and angiogenesis when co-injected as xenografts with a variety of tumor cell types and are established to maintain their myofibroblast-like phenotype when grown in culture [11]
Summary
The use of transcriptomics and proteomics to understand cellular function has been pivotal in advancing our knowledge of the molecular basis of disease processes, and the combined use of these approaches is beginning to highlight discord between the control of gene expression at the levels of transcription and translation. It is becoming clear that cellular levels of tRNAs are key to the control of gene expression in a number of different contexts. The availability of certain tRNAs may be controlled in the cell in order to regulate the efficiency of translation of certain gene transcripts. This may, in turn, allow the cell to regulate the activity of certain pathways [2]. Proliferating cells have increased levels of tRNAs that are specific for codons overrepresented in pathways required for proliferation. A number of publications have demonstrated that tRNA levels may be increased in cancer [3,4,5], and it was previously unknown whether this was a cause or consequence of carcinogenesis, recent work from
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