The “Self-eating” of cancer-associated fibroblast: A potential target for cancer

Chen, Yan; Zhang, Xiaozhen; Yang, Hanshen; Liang, Tingbo; Bai, Xueli

doi:10.1016/j.biopha.2023.114762

Cited by 8 publications

(6 citation statements)

References 231 publications

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“…CAFs are one of the most prominent and active components in the lung cancer microenvironment, and the enhancement of autophagy in CAFs has been shown to play a role in the malignant phenotype of human tumors. Autophagy promotes tumor progress not only by providing nutrients to the cancerous cells but also by inducing EMT, angiogenesis, stemness, and metastatic dissemination of the cancer cells [ 33 ]. Yuan et al demonstrated that the nucleosides are secreted by CAFs through autophagy increased glucose utilization and promoted growth of pancreatic ductal adenocarcinoma [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer

Zhou,

Qu,

Zhou

et al. 2024

J Exp Clin Cancer Res

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Background Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, and mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage is an important molecular event in oxidative stress. In lung cancer, the normal fibroblasts (NFs) are activated as cancer-associated fibroblasts (CAFs), and act in the realms of the tumor microenvironment (TME) with consequences for tumor growth and metastasis. However, its activation mechanism and whether it participates in tumor metastasis through antioxidative stress remain unclear. Methods The role and signaling pathways of tumor cell derived extracellular vesicles (EVs) activating NFs and the characteristic of induced CAFs (iCAFs) were measured by the transmission electron microscopy, nanoparticle tracking analysis, immunofluorescence, collagen contraction assay, quantitative PCR, immunoblotting, luciferase reporter assay and mitochondrial membrane potential detection. Mitochondrial genome and single nucleotide polymorphism sequencing were used to investigate the transport of mtDNA from iCAFs to ρ0 cells, which were tumor cells with mitochondrial dysfunction caused by depletion of mtDNA. Further, the effects of iCAFs on mitochondrial function, growth and metastasis of tumor cells were analysed in co-culture models both in vitro and in vivo, using succinate dehydrogenase, glutathione and oxygen consumption rate measurements, CCK-8 assay, transwell assay, xenotransplantation and metastasis experiments as well as in situ hybridization and immunohistochemistry. Results Our findings revealed that EVs derived from high-metastatic lung cancer cells packaged miR-1290 that directly targets MT1G, leading to activation of AKT signaling in NFs and inducing NFs conversion to CAFs. The iCAFs exhibit higher levels of autophagy and mitophagy and more mtDNA release, and reactive oxygen species (ROS) could further promote this process. After cocultured with the conditioned medium (CM) of iCAFs, the ρ0 cells may restore its mitochondrial function by acquisition of mtDNA from CAFs, and further promotes tumor metastasis. Conclusions These results elucidate a novel mechanism that CAFs activated by tumor-derived EVs can promote metastasis by transferring mtDNA and restoring mitochondrial function of tumor cells which result in resistance of oxidative stress, and provide a new therapeutic target for lung cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer

Zhou,

Qu,

Zhou

et al. 2024

J Exp Clin Cancer Res

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“…Therefore, understanding the mechanisms underlining CAFs activation and exploiting them therapeutically is fundamental to uncover the key vulnerabilities of the tumor [ 39 ]. Besides cancer cells, stromal cells, and fibroblasts in particular, are also subjected to altered metabolism depending on the microenvironmental context, further increasing the heterogeneity and complexity of the cellular composition and cell behavior in the tumor microenvironment [ 21 , 37 , 38 , 39 , 40 ]. With their secretions, cancer cells corrupt the fibroblasts, which become activated fibroblasts (or CAFs), and these in turn undergo a metabolic switch to glycolysis, producing energy-rich metabolites that fuel the tumor mass [ 15 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanistic involvement of autophagy in CAFs reprogramming remains controversial, given its dichotomous role [ 21 , 50 , 51 ]. Autophagy in CAFs can either counteract cancer progression in the early stages of tumorigenesis or exert a tumor-promoting role in advanced stages [ 40 ]. Moreover, CAFs localized in different parts of the tumor mass may display different levels of autophagy depending on the microenvironmental conditions they experience (e.g., hypoxia, nutrient deprivation, acidic pH, DNA damage, mitochondrial, and ER stresses) [ 21 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy

Ferraresi,

Girone,

Maheshwari

et al. 2024

IJMS

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One aspect of ovarian tumorigenesis which is still poorly understood is the tumor–stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.

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“…The tumor microenvironment (TME), which consists primarily of the extracellular matrix (ECM), is crucial to various aspects of tumor progression, such as tumorigenesis, metastasis, relapse and treatment resistance, making it a potential target for cancer therapies ( 1 , 2 ). The TME is a complex system comprising a range of cellular and noncellular elements, and cancer-associated fibroblasts (CAFs), which are highly abundant in the tumor stroma and exhibit potent regulatory effects on tumor growth ( 3 , 4 ). The induction of cell senescence through traditional cancer treatments is one of the most notable mechanisms of tumor suppression.…”

Section: Introductionmentioning

confidence: 99%

Cancer‑associated fibroblasts under therapy‑induced senescence in the tumor microenvironment (Review)

Zhang,

Lou,

Fang

et al. 2024

Exp Ther Med

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Current cancer treatments target tumor cells; however, the tumor microenvironment (TME) induces therapeutic resistance, tumor development and metastasis, thus rendering these treatments ineffective. Research on the TME has therefore concentrated on nonmalignant cells. Cancer-associated fibroblasts (CAFs) are a major TME component, which contribute to cancer progression due to their diverse origins, phenotypes and functions, including cancer cell invasion and migration, extracellular matrix remodeling, tumor metabolism modulation and therapeutic resistance. Standard cancer treatment typically exacerbates the senescence-associated secretory phenotype (SASP) of senescent cancer cells and nonmalignant cells that actively leak proinflammatory signals in the TME. Therapy-induced senescence may impair cancer cell activity and compromise treatment responsiveness. CAFs and SASP are well-studied in the formation and progression of cancer. The present review discusses the current data on CAF senescence caused by anticancer treatment and assesses how senescence-like CAFs affect tumor formation. The development of senolytic medication for aging stromal cells is also highlighted. Combining cancer therapies with senolytics may boost therapeutic effects and provide novel possibilities for research.

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The “Self-eating” of cancer-associated fibroblast: A potential target for cancer

Cited by 8 publications

References 231 publications

Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer

Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer

Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy

Cancer‑associated fibroblasts under therapy‑induced senescence in the tumor microenvironment (Review)

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