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Systemic inflammation in cachectic cancer patients: mechanisms and therapeutical strategies, a translational medicine approach

Abstract

Cachexia is a devastating wasting syndrome associated with poor prognosis and survival of cancer patients. Its aetiology has not been fully unveiled and the syndrome is frequently under diagnosed, despite afflicting around 40% of all cancer patients, and 80% of hospitalized patients. Chronic systemic inflammation is a main feature of cachexia, to which the white adipose tissue (WAT) plays a major contribution, as we have previously shown in animal models. It is our aim to address the role of WAT in the onset and maintenance of systemic inflammation in HUMAN cachexia, within a translational medicine approach. Preliminary results obtained over the last 24 months demonstrate that the adipose depots of cachectic cancer patients are infiltrated with immune cells, and actively secrete pro-inflammatory factors, similarly to what we described in animals. Bearing in mind that cachexia is systemic we have previously addressed (in models) the effect of an anti-inflammatory strategy encompassing the whole organism-regular sub-maximal intensity exercise, with very encouraging results. Therefore, a second goal of the project is to test the hypothesis that chronic exercise counteracts cachexia-associated WAT inflammation. We hypothesise (based on our animal studies) that, by decreasing WAT inflammatory factor secretion, the strategy will also reduce systemic inflammation, with reflexes in the liver, muscle, and in the tumour, which we also intend to examine. After informed consent, patients of the University Hospital shall be enrolled into 4 groups-cachectic cancer patients, non-cachectic cancer patients, cachectic patients, and Controls. The groups shall be further divided into sedentary (lst Phase) and trained (2nd Phase). The latter will be submitted to 6 wk endurance exercise (the protocol has been already tested and standardised for HU patients, after approval by the Ethics Committee). Plasma and tissue samples of both Sedentary and Trained patients will be collected during surgical procedure for tumour excision. We intend to investigate the effects of 1) cachexia and 2) the anti-inflammatory strategy on parameters regarding quality of life, and WAT, liver, skeletal muscle and tumour biology. Extensive biochemical, morphological and molecular analysis will be performed in collaboration with 6 different International (NIH; Boston University; University of Barcelona; University of Potsdam; University la Sapienza, CSIC) and 9 Brazilian (UNICAMP, UNIFESP, UMC, RDO-Diagnósticos, ICB-USP, FMUSP, IME-USP, EEFE-USP) institutions. The RESULTS will provide further insight on the mechanisms and molecular bases of cachexia, contributing for early and PRECISE DIAGNOSIS of the syndrome. The comprehensive screening of inflammation in cachexia intended shall warrant subsidy for the proposition of reliable markers, allowing not only the diagnosis of the syndrome, but also grading, and thus for the development of a diagnostic kit, for which we may require patent. Furthermore, the study aims at examining possible REGULATORS OF THE INFLAMMATORY SYNDROME, putting forward the hypothesis that the infiltrating immune cells in WAT, in the tumour and/or gut micro-biota may determinate the patient's disposition to develop cachexia, when compared with subjects matched for tumour type and staging who do not present the syndrome. Results of Phase 2 experiments shall very likely offer the possibility of TREATMENT FOR CACHEXIA, with strong impact in public health management, as exercise training is a low cost strategy, devoid of collateral effects, having been proven not to interfere with chemotherapy, but actually decreasing its deleterious side effects. Finally, the statistical analysis of the results and the establishment of all possible correlations will require the setting of a specific bioinformatics data platform. For that purpose two collaborating groups (University of Potsdam and IME-USP) will develop software's for which we intend to obtain patent. (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
Reversing Wasting Syndrome 
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Delgadez reversible 
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Scientific publications (28)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAMARGO, RODOLFO GONZALEZ; DOS REIS RICCARDI, DANIELA MENDES; TEIXEIRA RIBEIRO, HENRIQUE QUINTAS; CARNEVALI, JR., LUIZ CARLOS; DE MATOS-NETO, EMIDIO MARQUES; ENJIU, LUCAS; NEVES, RODRIGO XAVIER; CAROLA CORREIA LIMA, JOANNA DARCK; FIGUEREDO, RAQUEL GALVAO; MARTINS DE ALCANTARA, PAULO SERGIO; et al. NF-kappa Bp65 and Expression of Its Pro-Inflammatory Target Genes Are Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients. NUTRIENTS, v. 7, n. 6, p. 4465-4479, . (12/50079-0)
SIMOES, ESTEFANIA; CORREIA-LIMA, JOANNA; SARDAS, LEONARDO; STORTI, FELIPE; OTANI, THAIS ZELIA DOS SANTOS; VASQUES, DANIEL AUGUSTO CORREA; OTANI, VICTOR HENRIQUE OYAMADA; BERTOLAZZI, PAMELA; KOCHI, CRISTIANE; SEELAENDER, MARILIA; et al. Sex dimorphism in inflammatory response to obesity in childhood. International Journal of Obesity, v. 45, n. 4, p. 879-887, . (12/50079-0, 12/21677-6)
DE CASTRO, GABRIELA SALIM; ANDRADE, MARCIA FABIA; PINTO, FLAYDSON CLAYTON SILVA; FAIAD, JALINE ZANDONATO; SEELAENDER, MARILIA. mega-3 Fatty Acid Supplementation and Its Impact on Systemic Inflammation and Body Weight in Patients With Cancer Cachexia-A Systematic Review and Meta-Analysi. FRONTIERS IN NUTRITION, v. 8, . (12/50079-0, 20/07765-6)
DOS REIS RICCARDI, DANIELA MENDES; DAS NEVES, RODRIGO XAVIER; DE MATOS-NETO, EMIDIO MARQUES; CAMARGO, RODOLFO GONZALEZ; CAROLA CORREIA LIMA, JOANNA DARCK; RADLOFF, KATRIN; ALVES, MICHELE JOANA; FIGUEREDO COSTA, RAQUEL GALVAO; TOKESHI, FLAVIO; OTOCH, JOSE PINHATA; et al. Plasma Lipid Profile and Systemic Inflammation in Patients With Cancer Cachexia. FRONTIERS IN NUTRITION, v. 7, . (13/17178-7, 12/50079-0)
SAITO MIYAGI, MARIANA YASUE; LATANCIA, MARCELA TEATIN; TESTAGROSSA, LEONARDO ABREU; DE ANDRADE-OLIVEIRA, VINICIUS; PEREIRA, WELBERT OLIVEIRA; HIYANE, MEIRE IOSHIE; ENJIU, LUCAS MACERATESI; PISCIOTTANO, MARCUS; LEITE SEELAENDER, MARILIA CERQUEIRA; SARAIVA CAMARA, NIELS OLSEN; et al. Physical exercise contributes to cisplatin-induced nephrotoxicity protection with decreased CD4+T cells activation. Molecular Immunology, v. 101, p. 507-513, . (12/50079-0, 11/10349-5, 12/10435-1, 12/02270-2)
PINTO NETO, NELSON INACIO; DE PINHO MURARI, ARIENE SOARES; OYAMA, LILA MISSAE; OTOCH, JOSE PINHATA; MARTINS ALCANTARA, PAULO SERGIO; TOKESHI, FLAVIO; FIGUEREDO, RAQUEL GALVAO; ALVES, MICHELE JOANA; CAROLA CORREIA LIMA, JOANNA DARCK; DE MATOS-NETO, EMIDIO MARQUES; et al. Peritumoural adipose tissue pro-inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 9, n. 6, p. 1101-1108, . (12/50079-0)
SILVERIO, RENATA; LIRA, FABIO S.; OYAMA, LILA M.; OLLER DO NASCIMENTO, CLAUDIA M.; OTOCH, JOSE P.; ALCANTARA, PAULO S. M.; BATISTA, JR., MIGUEL L.; SEELAENDER, MARILIA. Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer. LIPIDS IN HEALTH AND DISEASE, v. 16, . (12/50079-0)
ALVES, MICHELE JOANA; FIGUEREDO, RAQUEL GALVAO; AZEVEDO, FLAVIA FIGUEIREDO; CAVALLARO, DIEGO ALEXANDRE; PINTO NETO, NELSON INACIO; CAROLA LIMA, JOANNA DARCK; MATOS-NETO, EMIDIO; RADLOFF, KATRIN; RICCARDI, DANIELA MENDES; CAMARGO, RODOLFO GONZALEZ; et al. Adipose tissue fibrosis in human cancer cachexia: the role of TGF beta pathway. BMC CANCER, v. 17, . (12/50079-0)
BATISTA, JR., MIGUEL L.; HENRIQUES, FELIPE S.; NEVES, RODRIGO X.; OLIVAN, MIREIA R.; MATOS-NETO, EMIDIO M.; ALCANTARA, PAULO S. M.; MAXIMIANO, LINDA F.; OTOCH, JOSE P.; ALVES, MICHELE J.; SEELAENDER, MARILIA. Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 7, n. 1, p. 37-47, . (12/50079-0)
DE CASTRO, GABRIELA S.; SIMOES, ESTEFANIA; LIMA, JOANNA D. C. C.; ORTIZ-SILVA, MILENE; FESTUCCIA, WILLIAM T.; TOKESHI, FLIVIO; ALCANTARA, PAULO S.; OTOCH, JOSE P.; COLETTI, DARIO; SEELAENDER, MARILIA. Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle. CANCERS, v. 11, n. 9, . (16/02780-1, 12/50079-0, 16/13810-9, 16/12508-7, 17/12260-8)
COSTA, RAQUEL G. F.; CARO, PAULA L.; DE MATOS-NETO, EMIDIO M.; LIMA, JOANNA D. C. C.; RADLOFF, KATRIN; ALVES, MICHELE J.; CAMARGO, RODOLFO G.; PESSOA, ANA FLAVIA M.; SIMOES, ESTEFANIA; GAMA, PATRICIA; et al. Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 5, p. 1116-1127, . (12/50079-0)
GONCALVES, DANIELA CAETANO; LIRA, FABIO SANTOS; YAMASHITA, ALEX SHIMURA; CARNEVALI JUNIOR, LUIZ CARLOS; EDER, ROBSON; LAVIANO, ALESSANDRO; LEITE SEELAENDER, MARILIA CERQUEIRA. Liver lipid metabolism disruption in cancer cachexia is aggravated by cla supplementation -induced inflammation. Clinical Nutrition, v. 38, n. 5, p. 2219-2230, . (12/50079-0)
SIMOES, ESTEFANIA; CORREIA-LIMA, JOANNA; CALFAT, ELIE LEAL DE BARROS; OTANI, THAIS ZELIA DOS SANTOS; VASQUES, DANIEL AUGUSTO CORREA; OTANI, VICTOR HENRIQUE OYAMADA; BERTOLAZZI, PAMELA; KOCHI, CRISTIANE; SEELAENDER, MARILIA; UCHIDA, RICARDO RIYOITI. Sex-Dependent Dyslipidemia and Neuro-Humoral Alterations Leading to Further Cardiovascular Risk in Juvenile Obesity. FRONTIERS IN NUTRITION, v. 7, . (12/50079-0, 12/21677-6)
SAITO MIYAGI, MARIANA YASUE; SEELAENDER, MARILIA; CASTOLDI, ANGELA; DE ALMEIDA, DANILO CANDIDO; NOVA BACURAU, ALINE VILLA; ANDRADE-OLIVEIRA, VINICIUS; ENJIU, LUCAS MACERATESI; PISCIOTTANO, MARCUS; HAYASHIDA, CAROLINE YURI; HIYANE, MEIRE IOSHIE; et al. Long-Term Aerobic Exercise Protects against Cisplatin-Induced Nephrotoxicity by Modulating the Expression of IL-6 and HO-1. PLoS One, v. 9, n. 10, . (12/02270-2, 12/10435-1, 11/10349-5, 12/50079-0)
DE JESUS, JOYCE DE CASSIA ROSA; MURARI, ARIENE SOARES DE PINHO; RADLOFF, KATRIN; DE MORAES, RUAN CARLOS MACEDO; FIGUEREDO, RAQUEL GALVAO; PESSOA, ANA FLAVIA MARCAL; ROSA-NETO, JOSE CESAR; MATOS-NETO, EMIDIO MARQUES; ALCANTARA, PAULO S. M.; TOKESHI, FLAVIO; et al. Activation of the Adipose Tissue NLRP3 Inflammasome Pathway in Cancer Cachexia. FRONTIERS IN IMMUNOLOGY, v. 12, . (12/50079-0)
SILVERIO, RENATA; GONCALVES, DANIELA CAETANO; ANDRADE, MARCIA FABIA; SEELAENDER, MARILIA. Coronavirus Disease 2019 (COVID-19) and Nutritional Status: The Missing Link?. ADVANCES IN NUTRITION, v. 12, n. 3, p. 682-692, . (12/50079-0)
BIONDO, LUANA A.; BATATINHA, HELENA A.; SOUZA, CAMILA O.; TEIXEIRA, ALEXANDRE A. S.; SILVEIRA, LOREANA S.; ALONSO-VALE, MARIA I.; OYAMA, LILA M.; ALVES, MICHELE J.; SEELAENDER, MARILIA; NETO, JOSE C. R.. Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue. FRONTIERS IN PHARMACOLOGY, v. 9, . (13/09367-4, 12/50079-0)
MARINHO, RODOLFO; ALCANTARA, PAULO S. M.; OTTOCH, JOSE P.; SEELAENDER, MARILIA. Role of Exosomal MicroRnAs and myomiRs in the Development of Cancer Cachexia-Associated Muscle Wasting. FRONTIERS IN NUTRITION, v. 4, . (16/19639-0, 12/50079-0)
DE MATOS-NETO, EMIDIO M.; LIMA, JOANNA D. C. C.; DE PEREIRA, WELBERT O.; FIGUEREDO, RAQUEL G.; RICCARDI, DANIELA M. DOS R.; RADLOFF, KATRIN; DAS NEVES, RODRIGO X.; CAMARGO, RODOLFO G.; MAXIMIANO, LINDA F.; TOKESHI, FLAVIO; et al. Systemic Inflammation in Cachexia - Is Tumor Cytokine Expression Profile the Culprit?. FRONTIERS IN IMMUNOLOGY, v. 6, . (12/10129-8, 12/50079-0)
LIMA, JOANNA D. C. C.; SIMOES, ESTEFANIA; DE CASTRO, GABRIELA; MORAIS, MYCHEL RAONY P. T.; DE MATOS-NETO, EMIDIO M.; ALVES, MICHELE J.; PINTO, I, NELSON; FIGUEREDO, RAQUEL G.; ZORN, TELMA M. T.; FELIPE-SILVA, ALOISIO S.; et al. Tumour-derived transforming growth factor-beta signalling contributes to fibrosis in patients with cancer cachexia. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 5, p. 1045-1059, . (16/04000-3, 12/50079-0)
CAMARGO, RODOLFO GONZALEZ; TEIXEIRA RIBEIRO, HENRIQUE QUINTAS; GERALDO, MURILO VIEIRA; MATOS-NETO, EMIDIO; NEVES, RODRIGO XAVIER; CARNEVALI, JR., LUIZ CARLOS; DONATTO, FELIPE FEDRIZZI; ALCANTARA, PAULO S. M.; OTTOCH, JOSE P.; SEELAENDER, MARILIA. Cancer Cachexia and MicroRNAs. Mediators of Inflammation, . (12/50079-0)
PINTO, NELSON INACIO; CARNIER, JUNE; OYAMA, LILA M.; OTOCH, JOSE PINHATA; ALCANTARA, PAULO SERGIO; TOKESHI, FLAVIO; NASCIMENTO, CLAUDIA M.. Cancer as a Proinflammatory Environment: Metastasis and Cachexia. Mediators of Inflammation, . (12/50079-0)
LIRA, FABIO S.; ANTUNES, BARBARA DE M. M.; SEELAENDER, MARILIA; ROSA NETO, JOSE C.. The therapeutic potential of exercise to treat cachexia. Current Opinion in Supportive and Palliative Care, v. 9, n. 4, p. 317-324, . (13/09367-4, 12/50079-0)
NEVES, RODRIGO X.; ROSA-NETO, JOSE CESAR; YAMASHITA, ALEX S.; MATOS-NETO, EMIDIO M.; RICCARDI, DANIELA M. R.; LIRA, FABIO S.; BATISTA, JR., MIGUEL L.; SEELAENDER, MARILIA. White adipose tissue cells and the progression of cachexia: inflammatory pathways. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 7, n. 2, p. 193-203, . (12/50079-0)
YAMASHITA, ALEX SHIMURA; DAS NEVES, RODRIGO XAVIER; ROSA-NETO, JOSE CESAR; LIRA, FABIO DOS SANTOS; BATISTA, JR., MIGUEL LUIS; ALCANTARA, PAULO SERGIO; OTOCH, JOSE PINHATA; SEELAENDER, MARILIA. White adipose tissue IFN-gamma expression and signalling along the progression of rodent cancer cachexia. CYTOKINE, v. 89, n. SI, p. 122-126, . (12/50079-0)
LIRA, FABIO SANTOS; ROSA NETO, JOSE CESAR; SEELAENDER, MARILIA. Exercise training as treatment in cancer cachexia. APPLIED PHYSIOLOGY NUTRITION AND METABOLISM, v. 39, n. 6, p. 679-686, . (12/50079-0)
GONCALVES, RENATA DE CASTRO; FREIRE, PAULA PACCIELLI; COLETTI, DARIO; SEELAENDER, MARILIA. Tumor Microenvironment Autophagic Processes and Cachexia: The Missing Link?. FRONTIERS IN ONCOLOGY, v. 10, . (20/09146-1, 12/50079-0, 20/07765-6)
DE CASTRO, GABRIELA S.; CORREIA-LIMA, JOANNA; SIMOES, ESTEFANIA; ORSSO, CAMILA E.; XIAO, JINGJIE; GAMA, LEONARDO R.; GOMES, SILVIO P.; GONCALVES, DANIELA CAETANO; COSTA, RAQUEL G. F.; RADLOFF, KATRIN; et al. Myokines in treatment-naive patients with cancer-associated cachexia. Clinical Nutrition, v. 40, n. 4, p. 2443-2455, . (16/12508-7, 12/50079-0, 16/13810-9, 13/25207-7, 16/02780-1)

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