HIF‐1α is necessary for activation and tumour‐promotion effect of cancer‐associated fibroblasts in lung cancer

Zhang, Yana; Bian, Yangyang; Wang, Yuan; Wang, Yuanyuan; Duan, Xixi; Han, Yuning; Zhang, Lijing; Wang, Fei; Gu, Zhuoyu; Qin, Zhihai

doi:10.1111/jcmm.16556

Cited by 34 publications

(29 citation statements)

References 51 publications

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“…Tumor-induced ROS-mediated “pseudo-hypoxia” in CAFs leads to the accumulation of HIF1α and enhanced aerobic glycolysis ( 173 , 174 ). Furthermore, high expression of HIF1α in CAFs induces protein expression in myofibroblasts in CAFs, and inhibition or knockout of HIF1α improves their phenotype ( 175 ). Stimulation by TGF-β or PDGF also suppresses IDH3 expression and decreases 2-oxoglutarate in fibroblasts, resulting in HIF1α accumulation and regulating fibroblast differentiation into CAFs ( 176 ).…”

Section: Discussionmentioning

confidence: 99%

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment

et al. 2022

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Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechanisms of ascorbic acid on cancer, including the role of ascorbic acid concentration. In addition, we present future perspectives on the effects of ascorbic acid on cancer cells and the CAF microenvironment. Ascorbic acid has a variety of effects, which contributes to the complexity of these effects. Oral administration of ascorbic acid results in low blood concentrations (<0.2 mM) and acts as a cofactor for antioxidant effects, collagen secretion, and HIFα degradation. In contrast, intravenous treatment achieves large blood concentrations (>1 mM) and has oxidative-promoting actions that exert anticancer effects via reactive oxygen species. Therefore, intravenous administration at high concentrations is required to achieve the desired effects on cancer cells during treatment. Partial data on the effect of ascorbic acid on fibroblasts indicate that it may also modulate collagen secretion in CAFs and impart tumor-suppressive effects. Thus, future studies should verify the effect of ascorbic acid on CAFs. The findings of this review can be used to guide further research and clinical trials.

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Section: Discussionmentioning

confidence: 99%

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment

et al. 2022

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“…In addition, HIF-1α is also considered to be a protein essential for activating tumor growth. It was reported that, in tumor-associated fibroblasts (CAFs), HIF-1α activates the NF-κB signaling pathway causing an increase in the expression level of CCL5, which promotes tumor growth [ 31 ]. Probucol is a cholesterol-lowering drug with potent antioxidant properties.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HIF-1α Attenuates Silica-Induced Pulmonary Fibrosis

Niu

et al. 2022

IJERPH

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Background: Excessive accumulation of extracellular matrix is a key feature of pulmonary fibrosis (PF), and myofibroblasts are the main producers of extracellular matrix. Fibroblasts are the major source of myofibroblasts, but the mechanisms of transdifferentiation are unclear. Methods: In vitro, transforming growth factor-β1 was used to induce NIH-3T3 cell transdifferentiation. DMOG was used to increase hypoxia-inducible factor-1α subunit (HIF-1α) expression. KC7F2 and siRNA decreased HIF-1α expression. In vivo, silica particles were used to induce PF in C57BL/6N mice, and KC7F2 was used to reduce HIF-1α expression in C57BL/6N mice. Western blot was used to detect the expression of collagen type 1 alpha 1(COL1A1), α-smooth muscle actin (α-SMA), SMAD family member (SAMD) 3, Phospho-SMAD3 (PSMAD3), and HIF-1α. PCR was used to detect the expression of COL1A1, α-SMA, and HIF-1α. Immunohistochemistry was used to detect the expression of COL1A1 and HIF-1α. Results: In vitro, compared to the control group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression were elevated in the DMOG group, and COL1A1, α-SMA, PSMAD3, and HIF-1α expression were decreased in the KC7F2 group and siRNA group. Compared to the DMOG group, COL1A1, α-SMA, and PSMAD3 expression were decreased in the DMOG + SIS3 group. In vivo, compared to the saline group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression were increased in the pulmonary tissue of C57BL/6N mice in the silica group. Compared to the silica group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression and the degree of PF were decreased in the silica + KC7F2 group. Conclusion: Inhibition of HIF-1α reduced α-SMA, decreased COL1A1 expression, and attenuated the degree of PF in C57BL/6N mice. Therefore, HIF-1α may be a new target for the treatment of silica-induced PF.

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“…Similarly, NAC has been shown to decrease MCT4 in fibroblasts in co-culture with keratinocytes, breast and ovarian carcinoma cells, as well as in breast cancer patients ( 27 , 76 – 78 ). HIF-1α has been shown to be necessary for the tumor-promoting effects of CAFs in NSCLC ( 79 ), and ROS are important signaling molecules that sustain, in part, the metabolic symbiosis between CAFs and carcinoma cells ( 58 ). Treatment with either BAY 87-2243 or NAC induced apoptosis and decreased proliferation in co-cultured ADT carcinoma cells ( Figure 9B ).…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers

et al. 2022

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The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers.

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HIF‐1α is necessary for activation and tumour‐promotion effect of cancer‐associated fibroblasts in lung cancer

Cited by 34 publications

References 51 publications

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment

Inhibition of HIF-1α Attenuates Silica-Induced Pulmonary Fibrosis

Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers

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