TGF-β1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation

Jena, Bikash Chandra; Das, Chandan; Banerjee, Indranil; Bharadwaj, Deblina; Majumder, Ranabir; Das, Subhayan; Biswas, Angana; Kundu, Moumita; Roy, Pritam; Kundu, Chanakya Nath; Mandal, Mahitosh

doi:10.1016/j.yexcr.2022.113195

Cited by 28 publications

(15 citation statements)

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“…While FBP1 is mediated by transforming growth factor beta (TGF-β) in the tumour microenvironment [ 375 ], CAFs are the origin of TGF-β, and CAFs are the most abundant cells in the tumour stroma that are recruited by platelet-derived growth factor secreted through the tumour [ 376 ]. The emergence of CAFs generally means that tumours occupy a dominant position in their environment through the activation of GLUT1 [ 188 , 377 ], thereby increasing glucose absorption and MCT4-mediated lactate release, finally remodeling tumour metabolism [ 187 , 188 , 378 ] and promoting tumour progression and invasion [ 379 , 380 ]. Therefore, it is not difficult to explain why NK cells can play a role in the initial stage but lose their role in the promotion and progression of tumour development ( Figure 5 ).…”

Section: The Role Of Metabolic Plasticity Regulation In the Tumour Mi...mentioning

confidence: 99%

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Niu

et al. 2023

IJMS

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One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.

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Section: The Role Of Metabolic Plasticity Regulation In the Tumour Mi...mentioning

confidence: 99%

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Niu

et al. 2023

IJMS

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“…Sirtuin 3 (SIRT3)-dependent ROS production and HIF-1α stabilization upregulates the expression of glucose transporter GLUT1 and lactate transporter monocarboxylate transporter-4 (MCT4) in CAFs, thereby shuttling lactate from CAFs to cancer cells to promote anabolic processes and cell growth [ 84 ]. Moreover, hypoxia has been shown to enhance glycolysis and upregulate MCT4 expression via TGF-β1-induced autophagy in CAFs [ 85 ].…”

Section: Mechanisms Underlying Caf Regulation and Function In Hypoxiamentioning

confidence: 99%

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Kim

Choi

Yoo

et al. 2022

Cancers

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Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment. CAFs are highly sensitive to hypoxia and participates in the crosstalk with cancer cells. Hypoxic CAFs modulate several mechanisms that induce cancer malignancy, such as extracellular matrix (ECM) remodeling, immune evasion, metabolic reprogramming, angiogenesis, metastasis, and drug resistance. Key signaling molecules regulating CAFs in hypoxia include transforming growth factor (TGF-β) and hypoxia-inducible factors (HIFs). In this article, we summarize the mechanisms underlying the hypoxic regulation of CAFs and how hypoxic CAFs affect cancer development and progression. We also discuss the potential therapeutic strategies focused on targeting CAFs in the hypoxic tumor microenvironment.

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“…TGF-β1 has been accepted as a pivotal mediator in the communication between cancer cells and stromal cells, which regulates growth, motility, and malignant transformation [ 20 ]. CAFs are suggested to be derived from TGF-β1-mediated myofibroblast transition of local fibroblasts [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA

Chen

et al. 2023

Cell Death Discov.

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Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-β1 secretion from CCA cells, which activated CAFs via the phosphorylation of Smad2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-β1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-β1/Smad2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.

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TGF-β1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation

Cited by 28 publications

References 50 publications

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA

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