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

Grant number: 12/50079-0
Support type:Research Projects - Thematic Grants
Duration: July 01, 2013 - March 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Marilia Cerqueira Leite Seelaender
Grantee:Marilia Cerqueira Leite Seelaender
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Claudia Maria da Penha Oller Do Nascimento ; Emerson Franchini
Associated grant(s):17/21085-5 - 10th international SCWD conference on cachexia, sarcopenia and muscle wasting, AR.EXT
Associated scholarship(s):16/19639-0 - Role of tumor-derived microRNAs in inducing muscle mass loss in patients with Cancer Cachexia, BP.PD
16/13810-9 - Cachexia associated with cancer and lipid metabolism: can chronic exercise affect fatty acids location and profile in muscle?, BP.PD
13/25207-7 - Is inflammation resolution failing in adipose tissue of cachectic patients?, BP.DD
13/17178-7 - Adipose tissue heterogeneity in cachexia: lipid profile in subcutaneous and visceral tissue of cancer patients, BP.MS
13/17734-7 - Effect of aerobic exercise training on inflammatory infiltrating tumor in cachectic na non-cachectic patients, BP.PD

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 

Scientific publications (21)
(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)
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; MAXIMIANO, LINDA FERREIRA; MARTINS DE ALCANTARA, PAULO SERGIO; COLQUHOUN, ALISON; LAVIANO, ALESSANDRO; SEELAENDER, MARILIA. Plasma Lipid Profile and Systemic Inflammation in Patients With Cancer Cachexia. FRONTIERS IN NUTRITION, v. 7, JAN 31 2020. Web of Science Citations: 0.
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; CARA, DENISE C.; DA SILVA, ALOISIO S. F.; PEREIRA, WELBERT O.; MAXIMIANO, LINDA F.; DE ALCANTARA, PAULO S. M.; OTOCH, JOSE P.; TRINCHIERI, GIORGIO; LAVIANO, ALESSANDRO; MUSCARITOLI, MAURIZIO; SEELAENDER, MARILIA. Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 5, p. 1116-1127, OCT 2019. Web of Science Citations: 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, OCT 2019. Web of Science Citations: 1.
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.; TOKESHI, FLAVIO; OTOCH, JOSE P.; ALCANTARA, PAULO; CABRAL, FERNANDA J.; FERRO, EMER S.; LAVIANO, ALESSANDRO; SEELAENDER, MARILIA. 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, OCT 2019. Web of Science Citations: 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 SEP 2019. Web of Science Citations: 0.
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; SEELAENDER, MARILIA; OLLER DO NASCIMENTO, CLAUDIA MARIA. 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, DEC 2018. Web of Science Citations: 4.
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; AMANO, MARIANE TAMI. Physical exercise contributes to cisplatin-induced nephrotoxicity protection with decreased CD4+T cells activation. Molecular Immunology, v. 101, p. 507-513, SEP 2018. Web of Science Citations: 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, MAY 8 2018. Web of Science Citations: 1.
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, JAN 9 2018. Web of Science Citations: 11.
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, AUG 22 2017. Web of Science Citations: 6.
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; MARTINS DE ALCANTARA, PAULO SERGIO; OTOCH, JOSE PINHATA; BATISTA JUNIOR, MIGUEL LUIZ; SEELAENDER, MARILIA. Adipose tissue fibrosis in human cancer cachexia: the role of TGF beta pathway. BMC CANCER, v. 17, MAR 14 2017. Web of Science Citations: 15.
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, JAN 2017. Web of Science Citations: 3.
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, MAY 2016. Web of Science Citations: 17.
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, MAR 2016. Web of Science Citations: 29.
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; OTOCH, JOSE P.; GOLDSZMID, ROMINA; CAMARA, NIELS O. S.; TRINCHIERI, GIORGIO; DE ALCANTARA, PAULO S. M.; SEELAENDER, MARILIA. Systemic Inflammation in Cachexia - Is Tumor Cytokine Expression Profile the Culprit?. FRONTIERS IN IMMUNOLOGY, v. 6, DEC 24 2015. Web of Science Citations: 18.
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, DEC 2015. Web of Science Citations: 19.
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; MAXIMIANO, LINDA; OTOCH, JOSE; BATISTA, JR., MIGUEL LUIZ; PUESCHEL, GERHARD; SEELAENDER, MARILIA. 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, JUN 2015. Web of Science Citations: 11.
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, 2015. Web of Science Citations: 8.
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, 2015. Web of Science Citations: 17.
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; BRUM, PATRICIA CHAKUR; SARAIVA CAMARA, NIELS OLSEN; AMANO, MARIANE TAMI. 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 OCT 1 2014. Web of Science Citations: 16.
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, JUN 2014. Web of Science Citations: 29.

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