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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 8, DEC 21 2018.
• Web of Science Citations: 6

Abstract

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)

• FAPESP's process: 15/19259-0 - Effects of adipose tissue remodeling during cachexia in gastrointestinal cancer patients: potential role of TLR4 receptor during cachexia-induced browning of WAT
• Grantee: Miguel Luiz Batista Junior
• Support Opportunities: Regular Research Grants