Abstract
Simple SummaryMetabolic reprogramming is an emerging hallmark in cancer. Beside the malignant compartment, the tumor microenvironment also undergoes to a metabolic skewing, contributing to the neoplastic progression and metastasizing process. Growing evidence pointed out a central role for Transforming Growth Factor Beta (TGF-β) as a driver of these metabolic changes in multiple cellular targets in cancer. This review deals with very recent discoveries on TGF-β-mediated metabolic reprogramming of stromal and immune cell population within the tumor microenvironment. In particular, we scrutinized current literature to highlight relevant metabolic checkpoints in the TGF-β cascade that sustain tolerogenic programs in tumors.Overcoming tumor immunosuppression still represents one ambitious achievement for cancer immunotherapy. Of note, the cytokine TGF-β contributes to immune evasion in multiple cancer types, by feeding the establishment of a tolerogenic environment in the host. Indeed, it fosters the expansion and accumulation of immunosuppressive regulatory cell populations within the tumor microenvironment (TME), where it also activates resident stromal cells and enhances angiogenesis programs. More recently, TGF-β has also turned out as a key metabolic adjuster in tumors orchestrating metabolic pathways in the TME. In this review, we will scrutinize TGF-β-mediated immune and stromal cell crosstalk within the TME, with a primary focus on metabolic programs.
Highlights
Cumulative evidence over the years has clearly showed that the activation of TGF-β can flow to either proor anti-inflammatory responses depending on the peculiar environment in which it is acting
Cumulative13evofi-21 dence over the years has clearly showed that the activation of TGF-β can flow to either pro- or anti-inflammatory responses depending on the peculiar environment in which it is acting
The duality of TGF-β signaling is well-recognized in cancer where the triggering ofofththeecacnanoonniciaclalSmSmadadppatahthwwaya,y,bbuut taalslosoththeennoonn-c-caannoonnicicaal lMMAAPPKK-G-GTTPPaaseseoonnee,mmigighht t lelaedadtotobbooththtutummoor rpprorommootitoionnananddsusupppprersessisoionn. .DDesepsipteitea addiriercetctefeffefcetctoonntutummoor rclcolonneses tntthyhetnttpeehhyiegmpeeeeihg,mesesbfht,esosaofbtlebsoavroltlbsseveirtlssrsepeih,issrnpoThm,ipgnoTGmeupgGaFnelutaa-Fntlβttt-atohiβ,tntfoheis,gnftiesfoggtoitflongheortlineerherfomeiireTcfiogmaoTMcgenaosMnettEnsniltctEyt;ihlcti;ychcteiicoretcpidcnorpuduectnusurveithtisvierbstheilesuboiselntuoipstnepthmtdteuthmeduemteconemtoocntotoomrtuotsmroumfms(fmimF(omiiFitmroigmimtgrdummeudureneeruvennetevn2otal2e)oson.a)lusp.onduppmdppfmuepfrunenersenntcssttcbiistvoybiiveonyaenspcasptoocitoofnpifpngmumugloualonutalitntloisitponitsprlntseorlseoamcnamecandlelladlll
Summary
Corroborated evidence has highlighted the crucial contribution of the tumor microenvironment (TME) in cancer progression. Most malignant cells depend on glycolysis for the ATP production, even under aerobic conditions (aerobic glycolysis) [2] This tumoral propensity to metabolize glucose anaerobically rather than aerobically is called Warburg effect. Even though the first suggestions indicated an impairment in oxidative metabolism, consistent evidence later on showed that a tumoral metabolic reprogramming is responsible for an increase of glucose metabolism despite an intact respiratory chain activity [4]. These mitochondrial independent anabolic pathways, including pentose-phosphate based nucleotide and NADPH synthesis, and Krebs cycle intermediates contribute to maintain cancer progression [5]. We will resume recent data on the TGF-β mediated TME metabolic reprogramming during tumoral development
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