Proteomic analysis in tumor microenvironment of cachectic patients: Understanding biological pathways and molecular mechanisms in cachexia.

Author(s)

Joanna Darck Carola Correia Lima

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2020-07-16

Examining board members

Marilia Cerqueira Leite Seelaender; Roger Chammas; Patricia Gama; Jose Pinhata Otoch

• Advisor: Marilia Cerqueira Leite Seelaender

Abstract

Cachexia is a paraneoplastic syndrome related with poor prognosis. Cachexia is characterised by muscle wasting with or without loss of adipose tissue. CAC is driven by multiple association of metabolic changes including reduced food intake, enhanced energy expenditure and inflammation. The aim of the present study was to characterize proteins altered in the tumour and respective the molecular mechanisms involved in cachexia. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Proteomic analysis was performed. 71 proteins were statistically significantly different between the groups (p value<0.05). Gene Ontology analysis showed that their majority consisted of proteins related with energetic and protein metabolism, oxidative stress, matrix extracellular remodelling and cellular maintenance. In order to increase the knowledge of the mechanisms involved in the fibrosis and oxidative stress, we show the presence of collagen deposition in the tumour, activation of alfa-SMA, vimentin and genes related to oxidative stress. Our results demonstrate TGF- &#946 pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF- &#946 induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). On the other hand, we speculate that these changes may be altered in response to hypoxia in tumor microenvironment of cachectic patients. Furthermore, the results provide insight on the adoption of tumour sample analysis for precocious diagnosis of the syndrome. (AU)

• FAPESP's process: 16/02780-1 - Molecular analysis in the tumor microenvironment of cachectic patients: A search of markers for early diagnosis of the syndrome
• Grantee: Joanna Darck Carola Correia Lima
• Support Opportunities: Scholarships in Brazil - Doctorate