The clinical significance of CXCL5 in non-small cell lung cancer

Wu, Kui; Yu, Shengnan; Liu, Qian; Bai, Xia; Zheng, Xinhua; Wu, Kongming

doi:10.2147/ott.s148772

Cited by 39 publications

(29 citation statements)

References 59 publications

(37 reference statements)

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“…As a confirmation, immunofluorescent staining and IHC showed increased CXCL5 expression in CAFs. In addition, it was demonstrated that nonsmall cell lung cancer, melanoma and CRC tumor cell lines also highly expressed CXCL5 which mold tumor microenvironment . Therefore, it seemed that CXCL5 was with diverse origins.…”

Section: Discussionmentioning

confidence: 99%

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Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

146

131

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Cancer‐associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death‐ligand 1 (PD‐L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of α‐SMA and PD‐L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD‐L1 expression. Further analyses showed that CAFs promoted PD‐L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD‐L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD‐L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD‐L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD‐L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p‐AKT were found to be positively correlated with PD‐L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.

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Section: Discussionmentioning

confidence: 99%

“…In addition, it was demonstrated that nonsmall cell lung cancer, melanoma and CRC tumor cell lines also highly expressed CXCL5 which mold tumor microenvironment. 17,25,26 Therefore, it seemed that CXCL5 was with diverse origins. Taken together, these data indicated an intriguing effect of CXCL5 in melanoma and CRC tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

146

131

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“…Only recently has the clinical significance of CXCL5 in lung cancer been suggested. The serum level of CXCL5 is significantly elevated in patients with non-small cell lung carcinoma (NSCLC) and CXCL5 immunoreactivity is enhanced in lung cancer tissue (53). Furthermore, CXCL5 expression correlates with the histologic grade, tumor size, lymph node metastasis, overall survival, and progression-free survival in patients with NSCLC (53).…”

Section: Discussionmentioning

confidence: 99%

Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer

et al. 2018

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Although lungs are densely innervated by the peripheral nervous system (PNS), the role of the PNS in the progression of lung cancer is unknown. In this study, we report that mouse adult Schwann cells (SC), the principal glial cells of the PNS, can regulate the motility of lung cancer cells and the formation of metastases SCs promoted epithelial-to-mesenchymal transition (EMT) and the motility of two lung cancer cell lines by increasing expression of Snail and Twist in tumor cells; blocking of Snail and Twist expression abolished SC-induced motility of tumor cells. SC-derived CXCL5 was responsible for EMT in lung cancer cells, as the inhibition of CXCL5 or its receptor CXCR2 reduced SC-induced expression of Snail and Twist and reduced motility in tumor cells. CXCL5/CXCR2 binding activated the PI3K/AKT/GSK-3β/Snail-Twist signaling pathway in lung cancer cells, and the PI3K inhibitor blocked CXCL5-dependent phosphorylation of AKT and GSK-3β, reduced expression of Snail/Twist, and limited tumor cell invasiveness. SC conditioning of tumor cells prior to their injection into mice significantly increased the formation of metastases in the regional lymph nodes. In summary, SCs can regulate the CXCL5/CXCR2/PI3K/AKT/GSK-3β/Snail-Twist pathway to promote EMT, invasiveness, and metastatic potential of lung cancer cells. Our results reveal a new role of the PNS in the functional organization of the tumor microenvironment and tumor progression. This study increases our understanding of how nerves and, in particular, specific glial cells, Schwann cells, in the peripheral nervous system, may help promote tumor growth and metastasis. .

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“…In addition to the aforementioned inflammatory markers, there were other candidate genes for which there was enhanced expression in the TNFα array in rHypoE‐7 neurones (Figure A). Many up‐regulated genes are part of the C‐X‐X motif ligand family, including Cxcl1, Cxcl2 and Cxcl5, which are chemokines involved in inflammasome activation and recruitment of immune cells . Cx3 cl1, also known as fractalkine, is induced in the hypothalamic neurones of diet‐induced obese mice, and was shown to have a role in hypothalamic inflammation and diet‐induced glucose intolerance .…”

Section: Discussionmentioning

confidence: 99%

“…Many upregulated genes are part of the C-X-X motif ligand family, including Cxcl1, Cxcl2 and Cxcl5, which are chemokines involved in inflammasome activation and recruitment of immune cells. 53,54 Cx3 cl1, also known as fractalkine, is induced in the hypothalamic neurones of diet-induced obese mice, and was shown to have a role in hypothalamic inflammation and diet-induced glucose intolerance. 55 Toll-interacting protein (Tollip) is another factor induced by TNFα in rHypoE-7 neurones.…”

Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways

Clemenzi

Wellhauser

Aljghami

et al. 2019

J Neuroendocrinology

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The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over‐nutrition is tumour necrosis factor (TNF)α. Using immortalised embryonic rat and mouse hypothalamic cell lines (rHypoE‐7 and mHypoE‐46) that express orexigenic neuropeptide Y and agouti‐related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNFα exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL‐1 TNFα for 4 hours. Furthermore, neurones pre‐exposed to TNFα (50 ng mL‐1) for 6 or 16 hours exhibited a significant reduction in phosphorylated Akt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling‐related genes was also decreased with exposure to TNFα. TNFα significantly increased mRNA expression of IκBα, Tnfrsf1a and IL6 at 4 and 24 hours, activating a pro‐inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit β (IKK‐β) inhibitor, PS1145, demonstrated that TNFα‐induced neuroinflammatory marker expression occurs through the IKK‐β/nuclear factor‐kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti‐inflammatory treatment to reverse insulin resistance, neurones were treated with TNFα and PS1145, which did not significantly restore the TNFα‐induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNFα causes cellular insulin resistance and inflammation marker expression in the rHypoE‐7 and mHypoE‐46 neurones, consistent with effects seen with TNFα in peripheral tissues. It also mimics insulin‐ and palmitate‐induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity‐induced cytokine expression.

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The clinical significance of CXCL5 in non-small cell lung cancer

Cited by 39 publications

References 59 publications

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer

Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways

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