The expression landscape of cachexia‐inducing factors in human cancers
Abstract Background Cachexia is a multifactorial syndrome highly associated with specific tumour types, but the causes of variation in cachexia prevalence and severity are unknown. While circulating plasma mediators (soluble cachectic factors) derived from tumours have been implicated with the patho...
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doaj-53427912aaf347d5bceb03b1abd7b3c52020-11-25T03:24:10ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092020-08-0111494796110.1002/jcsm.12565The expression landscape of cachexia‐inducing factors in human cancersPaula Paccielli Freire0Geysson Javier Fernandez1Diogo deMoraes2Sarah Santiloni Cury3Maeli Dal Pai‐Silva4Patrícia Pintor dosReis5Silvia Regina Rogatto6Robson Francisco Carvalho7Department of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilDepartment of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilDepartment of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilDepartment of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilDepartment of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilDepartment of Surgery and Orthopedics, Faculty of Medicine São Paulo State University, UNESP Botucatu BrazilDepartment of Clinical Genetics, University Hospital, Institute of Regional Health Research University of Southern Denmark Vejle DenmarkDepartment of Structural and Functional Biology, Institute of Biosciences São Paulo State University, UNESP Botucatu BrazilAbstract Background Cachexia is a multifactorial syndrome highly associated with specific tumour types, but the causes of variation in cachexia prevalence and severity are unknown. While circulating plasma mediators (soluble cachectic factors) derived from tumours have been implicated with the pathogenesis of the syndrome, these associations were generally based on plasma concentration rather than tissue‐specific gene expression levels. Here, we hypothesized that tumour gene expression profiling of cachexia‐inducing factors (CIFs) in human cancers with different prevalence of cachexia could reveal potential cancer‐specific cachexia mediators and biomarkers of clinical outcome. Methods First, we combined uniformly processed RNA sequencing data from The Cancer Genome Atlas and Genotype‐Tissue Expression databases to characterize the expression profile of secretome genes in 12 cancer types (4651 samples) compared with their matched normal tissues (2737 samples). We systematically investigated the transcriptomic data to assess the tumour expression profile of 25 known CIFs and their predictive values for patient survival. We used the Xena Functional Genomics tool to analyse the gene expression of CIFs according to neoplastic cellularity in pancreatic adenocarcinoma, which is known to present the highest prevalence of cachexia. Results A comprehensive characterization of the expression profiling of secreted genes in different human cancers revealed pathways and mediators with a potential role in cachexia within the tumour microenvironment. Cytokine‐related and chemokine‐related pathways were enriched in tumour types frequently associated with the syndrome. CIFs presented a tumour‐specific expression profile, in which the number of upregulated genes was correlated with the cachexia prevalence (r2: 0.80; P value: 0.002) and weight loss (r2: 0.81; P value: 0.002). The distinct gene expression profile, according to tumour type, was significantly associated with prognosis (P value ≤ 1.96 E‐06). In pancreatic adenocarcinoma, the upregulated CIF genes were associated with tumours presenting low neoplastic cellularity and high leucocyte fraction and not with tumour grade. Conclusions Our results present a biological dimension of tumour‐secreted elements that are potentially useful to explain why specific cancer types are more likely to develop cachexia. The tumour‐specific profile of CIFs may help the future development of better targeted therapies to treat cancer types highly associated with the syndrome.https://doi.org/10.1002/jcsm.12565Cachexia‐inducing factorsCancer genomicsGTExOmicsPan‐cancerTCGA |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paula Paccielli Freire Geysson Javier Fernandez Diogo deMoraes Sarah Santiloni Cury Maeli Dal Pai‐Silva Patrícia Pintor dosReis Silvia Regina Rogatto Robson Francisco Carvalho |
spellingShingle |
Paula Paccielli Freire Geysson Javier Fernandez Diogo deMoraes Sarah Santiloni Cury Maeli Dal Pai‐Silva Patrícia Pintor dosReis Silvia Regina Rogatto Robson Francisco Carvalho The expression landscape of cachexia‐inducing factors in human cancers Journal of Cachexia, Sarcopenia and Muscle Cachexia‐inducing factors Cancer genomics GTEx Omics Pan‐cancer TCGA |
author_facet |
Paula Paccielli Freire Geysson Javier Fernandez Diogo deMoraes Sarah Santiloni Cury Maeli Dal Pai‐Silva Patrícia Pintor dosReis Silvia Regina Rogatto Robson Francisco Carvalho |
author_sort |
Paula Paccielli Freire |
title |
The expression landscape of cachexia‐inducing factors in human cancers |
title_short |
The expression landscape of cachexia‐inducing factors in human cancers |
title_full |
The expression landscape of cachexia‐inducing factors in human cancers |
title_fullStr |
The expression landscape of cachexia‐inducing factors in human cancers |
title_full_unstemmed |
The expression landscape of cachexia‐inducing factors in human cancers |
title_sort |
expression landscape of cachexia‐inducing factors in human cancers |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2020-08-01 |
description |
Abstract Background Cachexia is a multifactorial syndrome highly associated with specific tumour types, but the causes of variation in cachexia prevalence and severity are unknown. While circulating plasma mediators (soluble cachectic factors) derived from tumours have been implicated with the pathogenesis of the syndrome, these associations were generally based on plasma concentration rather than tissue‐specific gene expression levels. Here, we hypothesized that tumour gene expression profiling of cachexia‐inducing factors (CIFs) in human cancers with different prevalence of cachexia could reveal potential cancer‐specific cachexia mediators and biomarkers of clinical outcome. Methods First, we combined uniformly processed RNA sequencing data from The Cancer Genome Atlas and Genotype‐Tissue Expression databases to characterize the expression profile of secretome genes in 12 cancer types (4651 samples) compared with their matched normal tissues (2737 samples). We systematically investigated the transcriptomic data to assess the tumour expression profile of 25 known CIFs and their predictive values for patient survival. We used the Xena Functional Genomics tool to analyse the gene expression of CIFs according to neoplastic cellularity in pancreatic adenocarcinoma, which is known to present the highest prevalence of cachexia. Results A comprehensive characterization of the expression profiling of secreted genes in different human cancers revealed pathways and mediators with a potential role in cachexia within the tumour microenvironment. Cytokine‐related and chemokine‐related pathways were enriched in tumour types frequently associated with the syndrome. CIFs presented a tumour‐specific expression profile, in which the number of upregulated genes was correlated with the cachexia prevalence (r2: 0.80; P value: 0.002) and weight loss (r2: 0.81; P value: 0.002). The distinct gene expression profile, according to tumour type, was significantly associated with prognosis (P value ≤ 1.96 E‐06). In pancreatic adenocarcinoma, the upregulated CIF genes were associated with tumours presenting low neoplastic cellularity and high leucocyte fraction and not with tumour grade. Conclusions Our results present a biological dimension of tumour‐secreted elements that are potentially useful to explain why specific cancer types are more likely to develop cachexia. The tumour‐specific profile of CIFs may help the future development of better targeted therapies to treat cancer types highly associated with the syndrome. |
topic |
Cachexia‐inducing factors Cancer genomics GTEx Omics Pan‐cancer TCGA |
url |
https://doi.org/10.1002/jcsm.12565 |
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