Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival in Cancer Cachexia Syndrome

Autor(es):Mostrar menos -

Henriques, Felipe ^{[1, 2]} ; Lopes, Magno A. ^[2] ; Franco, Felipe O. ^[2] ; Knobl, Pamela ^[2] ; Santos, Kaltinaitis B. ^[2] ; Bueno, Luana L. ^[2] ; Correa, Victor A. ^[2] ; Bedard, Alexander H. ^[1] ; Guilherme, Adilson ^[1] ; Birbrair, Alexander ^[3] ; Peres, Sidney B. ^[4] ; Farmer, Stephen R. ^[5] ; Batista, Jr., Miguel L. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Massachusetts, Med Sch, Program Mol Med, Worcester, MA 01605 - USA

^[2] Univ Mogi das Cruzes, Lab Adipose Tissue Biol, Integrated Grp Biotechnol, Sao Paulo - Brazil

^[3] Univ Fed Minas Gerais, Dept Pathol, Minas, Gerais - Brazil

^[4] Univ Estadual Maringa, Dept Physiol Sci, Maringa, Parana - Brazil

^[5] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 - USA

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 8, DEC 21 2018.
• Citações Web of Science: 6

Resumo

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4(-/-) mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4(-/-) mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in TLR4(-/-) TB mice. Moreover, the treatment was effective in prolonging survival and attenuating tumor mass growth when compared to non-treated-TB animals. Furthermore, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising target for novel anti-cachexia therapies. (AU)

• Processo FAPESP: 10/51078-1 - Bases moleculares da caquexia: adipogênese e remodelagem da matriz extracelular do tecido adiposo branco de pacientes com câncer gastrointestinal
• Beneficiário: Miguel Luiz Batista Junior
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/19259-0 - Repercussões do remodelamento do tecido adiposo durante a síndrome de caquexia em pacientes com câncer gastrointestinal: potencial envolvimento do receptor TLR4 na modulação do browning no TAB
• Beneficiário: Miguel Luiz Batista Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular