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| Author(s): |
Estefanía Simoes Fernández
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2021-05-28 |
| Examining board members: |
Marilia Cerqueira Leite Seelaender;
Alison Colquhoun;
Maria Cassia Jacintho Mendes Corrêa;
Guilherme Alves Lepski
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| Advisor: | Marilia Cerqueira Leite Seelaender |
| Abstract | |
Cachexia is a clinically challenging multifactorial and multiorgan syndrome, associated with poor outcome in cancer patients, and characterized by inflammation and loss of appetite, and the mechanisms underlying its symptoms have not been fully described. The syndrome leads to central nervous system (CNS) dysregulation and to neuroinflammation, with impact on neural circuits controlling feeding behaviour and body composition. The aim of the present study was to simultaneously characterise the peripheral concentration of hormones, neuropeptides and cytokines. Furthermore, we examined CNS morphology and functionality, neuronal morphology and central immune cell profile in cachectic patients. Colorectal cancer patients with (cachectic cancer- CC; n=39) or without cachexia (weight-stable, WSC; n=31) were enrolled. The protein content of circulating cytokines, hormones and neuropeptides was measured with Luminex ®x MAP technology and/or ELISA. Central-peripheral crosstalk was concomitantly investigated in a rodent model of cachexia, by measuring neuropeptide and brain receptor mRNA (quantitative RT-PCR). The evaluation of the changes affecting the CNS was performed using in vivo structural magnetic resonance imaging (Philips Achieva Scanner 3 Tesla) and post-mortem neuropathological analyses (Qupath Software). The results show that cachectic cancer patients present reduced concentration of circulating appetite control-related hormones [insulin (-25%), leptin (-50%), amylin (-17%), GIP (-46%) and GLP-1 (-26%)], and of neuropeptides [ β -Endorphin (-36%), neurotensin (-36%), oxytocin (-37%), α -MSH (-42%) and MCH (-17%)] in comparison with WSC. The expression of NPY (+28%) and of Leptin receptor (+20%) was increased in the hypothalamus of tumour-bearing animals. Furthermore, the human CNS presented structural and functional differences in the gray matter (GM) of the regions such as the caudate nucleus, putamen, insula, orbitofrontal cortex, among others (pFWE <0.05). Also, CC showed abnormal neuronal morphology, neuronal density, microglia/macrophage burden and astrocyte profile disruption (p <0.05). In conclusion, these novel findings show that wasting in cachexia is accompanied by disrupted counterregulat ory capacity, as the adaptive changes in circulating hormones and neuropeptides occurring in WSC in response to cancer, fail in CC to bear correlation with the inflammatory status. The increased expression of NPY and leptin receptors in the cachectic rats may suggest a compensatory response to decreased signal input during cachexia. The results indicate that cachexia compromises CNS morphology mostly causing changes in GM of cachectic patients, leading to alterations in regional volume patterns, functional connectivity, neuronal morphology and neuroglia profile disruptions that may all contribute to the loss of homeostatic function control and to deficient information processing, as well as to metabolic and behavioural derangements in human cachexia. To our knowledge, this is the first study to provide the characterization of the cachectic human brain. The findings contribute to the basis for potential proposition of therapeutic strategies in cancer cachexia. (AU) | |
| FAPESP's process: | 16/12508-7 - Hypothalamic changes related to the syndrome of cachexia associated with cancer: morphological analysis and histological, molecular, cellular and systemic central nervous system study |
| Grantee: | Estefania Simoes Fernandez |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |