Contextual determinants of TGFβ action in development, immunity and cancer

David, Charles J.; Massagué, Joan

doi:10.1038/s41580-018-0007-0

Cited by 638 publications

(698 citation statements)

References 201 publications

Supporting

Mentioning

655

Contrasting

Unclassified

Order By: Relevance

“…In the liver, TIME TGFβ may suppress anti-tumour immune responses in several ways, by promoting Th2 vs Th1 response, by favouring the differentiation of macrophages into pro-tumorigenic M2-type and of naive CD4 + T-cells into Tregs, and by inhibiting the effector function of CD8 + T cells and NK cells. 96 TGFβ is also directly involved in the development and progression of solid tumours. In liver tissue it plays a major role in liver inflammation and fibrosis progression, through the activation of HSCs, which are the main producers of TGFβ.…”

Section: Soluble Mediators Of the Tumour Microenvironmentmentioning

confidence: 99%

“…In liver tissue it plays a major role in liver inflammation and fibrosis progression, through the activation of HSCs, which are the main producers of TGFβ. 96 In the early stages of hepatocarcinogenesis, TGFβ has tumour suppressive functions inhibiting cell proliferation and stimulating apoptosis. 97 Conversely, after cell transformation has occurred, the cytokine promotes apoptosis resistance and cell proliferation 97 together supporting tumour progression and dissemination.…”

Section: Soluble Mediators Of the Tumour Microenvironmentmentioning

confidence: 99%

“…TGFβ is also directly involved in the development and progression of solid tumours. In liver tissue it plays a major role in liver inflammation and fibrosis progression, through the activation of HSCs, which are the main producers of TGFβ . In the early stages of hepatocarcinogenesis, TGFβ has tumour suppressive functions inhibiting cell proliferation and stimulating apoptosis .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

View full text Add to dashboard Cite

The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high‐resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.

show abstract

Section: Soluble Mediators Of the Tumour Microenvironmentmentioning

confidence: 99%

Section: Soluble Mediators Of the Tumour Microenvironmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

View full text Add to dashboard Cite

show abstract

“…TGFBs, activins, myostatin and nodal induce the phosphorylation of R-SMAD2 or 3, while BMPs mediate their activity through R-SMAD1, 5 or 8. All R-SMADs bind to SMAD4, an essential component for the generation of SMAD transcriptional responses [11][12][13] . Previous studies have demonstrated a role for some TGFβ ligands in myogenesis.…”

Section: A High Throughput Assay Identifies Novel Regulator Of Myoblamentioning

confidence: 99%

Auto-inhibition of myoblast fusion by cyclic receptor signalling

Sieiro

Melendez

Morin

et al. 2019

Preprint

View full text Add to dashboard Cite

Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair. The vast majority of molecules known to regulate myoblast fusion are necessary in this process. Here we uncover, through high-throughput in vitro assays and in vivo studies in the chicken embryo, that TGFβ (SMAD2/3-dependent) signalling acts as a molecular brake on muscle fusion. While constitutive activation of the pathway arrests fusion, its inhibition leads to a striking over-fusion phenotype. This dynamic control of TGFβ signalling in the embryonic muscle relies on a unique receptor complementation mechanism, prompted by the merging of myoblasts with myofibres, each carrying one component of the heterodimer receptor complex. The competence of myofibres to fuse is restored through endocytic degradation of activated receptors. Altogether, this study shows that muscle fusion is a self-regulated process that relies on cyclic TGFβ signalling to regulate its pace. MainMyoblast fusion occurs after muscle specification and early differentiation, themselves regulated by the Myogenic Regulatory Factors (MRFs) MYF5, MYOD and MYOG 1-3 . While MRF function is necessary for myoblast fusion 4 , terminal differentiation, including muscle contraction, can occur even if fusion is disrupted 5-7 . Work in Drosophila identified a number of molecules, mainly implicated in actin regulation, required for muscle fusion in this organism. A major advance was the demonstration that their homologs play similar function during vertebrate myogenesis 2,3,8 . Together with vertebrate-specific muscle fusion genes (e.g. Myomaker, Myomixer, JAM2-3) they constitute the "fusion machinery" necessary for the fusion of myoblasts to myofibres. Recent analyses we performed on myoblast fusion during embryonic development suggested that additional mechanisms must exert temporal and spatial control on the fusion machinery, modulating whether myoblasts and myofibres that are competent to fuse do so and at what pace 9 . The molecular underpinning of such control over fusion is completely unknown.

show abstract

“…[13] All these secreted substances together result in the enhancement of collagen deposition, the remodeling of ECM and the formation of dense stromal TME. [18] Apart from this, TGF-β also plays a substantial role in the recruitment, activation and infiltration of macrophages, myeloid-derived suppressor cells and regulatory T (Treg) cells in TME, especially in the induction of M2 macrophages polarization. [19] Therefore, we speculated that regulating the TGF-β signal pathway to inactivate CAFs and inhibit M2 polarization might remodel the TME and enhance the intratumor drug penetration.…”

Section: Introductionmentioning

confidence: 99%

Sequential Targeting TGF‐β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer

Pei

Liang

Huang

et al. 2019

Small

View full text Add to dashboard Cite

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF‐β) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF‐β and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential‐targeting strategy is developed, in which antifibrotic fraxinellone‐loaded CGKRK‐modified nanoparticles (Frax‐NP‐CGKRK) are constructed to regulate TGF‐β signaling and siRNA‐loaded lipid‐coated calcium phosphate (LCP) biomimetic nanoparticles (siKras‐LCP‐ApoE3) are applied to interfere with the oncogenic KRAS. Frax‐NP‐CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer‐associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras‐LCP‐ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential‐targeting strategy significantly elongates the lifespans of pancreatic tumor‐bearing animals, hence providing a promising approach for pancreatic cancer therapy.

show abstract

Contextual determinants of TGFβ action in development, immunity and cancer

Cited by 638 publications

References 201 publications

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Auto-inhibition of myoblast fusion by cyclic receptor signalling

Sequential Targeting TGF‐β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer

Contact Info

Product

Resources

About