Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway

Wang, Limin; Cao, Limin; Wang, Huimin; Liu, Boning; Zhang, Qicheng; Meng, Zhaowei; Wu, Xiang; Zhou, Qinghua; Xu, Ke

doi:10.18632/oncotarget.18814

Cited by 133 publications

(121 citation statements)

References 45 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…8 In our previous study, we isolated and grew CAF from lung cancer specimens, and demonstrated that CAF promote metastasis and EMT of lung cancer cells via IL-6 secretion and JAK2/STAT3 pathway activation. 11 This finding prompted us to further investigate the role of CAF in drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer‐associated fibroblasts were isolated from primary tumor tissue as previously described . CAF were cultured in DMEM/F12 medium supplemented with 10% FBS at 37°C, 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Cancer-associated fibroblasts were isolated from primary tumor tissue as previously described. 11 CAF were cultured in DMEM/F12 medium supplemented with 10% FBS at 37°C, 5% CO 2 . For the preparation of CAF-conditioned medium (CAF-CM), CAF were cultured for 48 hours; the CAF-CM was collected and centrifuged for 10 minutes at 1500 g to remove cell debris.…”

Section: Isolationandcultureofstromalfibroblastsmentioning

confidence: 99%

See 2 more Smart Citations

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Wang

Ren

et al. 2019

Cancer Science

Self Cite

View full text Add to dashboard Cite

Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts ( CAF ) are one of the key components of stromal cells. CAF have a great impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of CAF in cisplatin resistance of lung cancer cells. By using conditioned medium from CAF ( CAF ‐ CM ), we found that CAF decreased the sensitivity of lung cancer cells to cisplatin. RNA sequencing results showed that CAF expressed a higher level of Annexin A3 ( ANXA 3) than normal fibroblasts ( NF ), and CAF ‐ CM incubation increased the ANXA 3 level in lung cancer cells. Overexpression of ANXA 3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase ( JNK ), whereas knockdown of ANXA 3 increased cisplatin sensitivity. Further study showed that CAF ‐ CM enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the ANXA 3/ JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF ‐ CM and ANXA 3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA 3/ JNK pathway both in vitro and in vivo, suggesting ANXA 3 could be a potential therapeutic target for the treatment of chemoresistant cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Cancer‐associated fibroblasts were isolated from primary tumor tissue as previously described . CAF were cultured in DMEM/F12 medium supplemented with 10% FBS at 37°C, 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Section: Isolationandcultureofstromalfibroblastsmentioning

confidence: 99%

See 1 more Smart Citation

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Wang

Ren

et al. 2019

Cancer Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…This could possibly be one of the routes through which CSCs transform NGFs into CAFs; CSCs thus create a protumor growth niche by expanding the CAF pool in the TME. CAFs have also been shown to enhance the metastatic potential of lung cancers via IL-6/STAT3 signalling pathways [40]. Importantly, studies associated with STAT3 also showed its involvement in enhancing the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) [41].…”

Section: Discussionmentioning

confidence: 99%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

View full text Add to dashboard Cite

Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated Cancers 2020, 12, 56 2 of 16 β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

show abstract

“…In addition, conditions within the TM such as hypoxia and ROS within the TM milieu also contribute to the conversion of normal cells to pro-tumorigenic cells [168,169]. Through the expression and secretion of growth factors and cytokines and their receptors, CAFs impact cancer cell-associated processes such as inflammation, angiogenesis, migration, invasion, chemoresistance and immune evasion ( Figure 14) [79,[170][171][172][173]. Erez and colleagues demonstrated that normal fibroblasts can be induced to express inflammatory genes by carcinoma cells [174].…”

Section: Cancer-associated Fibroblasts and Carcinogenesismentioning

confidence: 99%

Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

Dzobo¹

2020

Preprint

View full text Add to dashboard Cite

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

show abstract

Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway

Cited by 133 publications

References 45 publications

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

Contact Info

Product

Resources

About