CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer

Miyake, Makito; Hori, Shunta; Morizawa, Yosuke; Tatsumi, Yoshihiro; Nakai, Yasushi; Anai, Satoshi; Torimoto, Kazumasa; Aoki, Katsuya; Tanaka, Nobumichi; Shimada, Kaoru; Konishi, Noboru; Toritsuka, Michihiro; Kishimoto, Toshifumi; Rosser, Charles J.; Fujimoto, Kiyohide

doi:10.1016/j.neo.2016.08.002

Cited by 178 publications

(202 citation statements)

References 43 publications

(52 reference statements)

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“…Remarkably, in several cell lines of epithelial origin, the top CDK8/19-coregulated NFκB targets included a family of related cytokines with tumor-promoting and proinflammatory activities: IL8, CXCL1, and CXCL2. These cytokines, ligands of CXCR1/2 receptors, are known to play key roles in the interactions of tumor cells with various stromal components of the tumor microenvironment (31,32). In particular, the induction of chemoresistance and metastasis in breast cancer xenografts treated with doxorubicin and cyclophosphamide has been associated with TNFα-induced NFκB-mediated transcription of CXCL1/2 (20).…”

Section: Discussionmentioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

130

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The nuclear factor-κB (NFκB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFκB show significant side effects, possibly due to sustained NFκB suppression. Drugs affecting induced, but not basal, NFκB activity may have the potential to provide therapeutic benefit without associated toxicity. NFκB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFκB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFα. On NFκB activation, CDK8/19 are corecruited with NFκB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NFκB includeIL8,CXCL1, andCXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFκB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFκB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

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Section: Discussionmentioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

130

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“…Western blotting was carried out as previously described. 23 The primary antibody for PD-L1 detection is described in Table S1. Mouse recombinant PD-L1 protein (Novoprotein) and T24 cell lysates were used as positive controls.…”

Section: Western Blottingmentioning

confidence: 99%

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

et al. 2019

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Despite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle‐invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony‐stimulating factor (GM‐CSF) to chemoimmunotherapy with programmed cell death protein‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 105 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non‐treated control (vehicle only); (ii) anti‐mPD‐L1 monotherapy; (iii) mGM‐CSF monotherapy; (iv) anti‐mPD‐L1 plus mGM‐CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti‐mPD‐L1; (vii) GC plus mGM‐CSF; and (viii) GC plus anti‐mPD‐L1 plus mGM‐CSF. After completing 2‐week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti‐mPD‐L1 and mGM‐CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti‐mPD‐L1, and mGM‐CSF resulted in longer LR‐free survival and cancer‐specific survival compared to those in other groups. These effects involved an immunotherapy‐related decrease in oncological properties such as tumor invasion capacity and epithelial‐mesenchymal transition. mGM‐CSF significantly decreased the accumulation of myeloid‐derived suppressor cells in both the blood and tumor microenvironment and blood interleukin‐6 levels. Supplementary GM‐CSF to neoadjuvant GC plus PD‐L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment.

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“…Additionally, CXCL1 has also been shown to contribute to radioresistance through inducing DNA damage repair in a ROS‐dependent manner in esophageal squamous cell carcinoma, indicating that CXCL1 might be a potential target for suppressing radioresistance in cancer therapy . Moreover, it has been noted that CXCL1 promotes tumorigenesis, progression, and recurrence in a range of cancers including bladder cancer, pancreatic cancer, and glioma . However, the functional role of CXCL1 in GBM radioresistance has not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies show that chemokines are critical for angiogenesis, hematopoiesis, tumorigenesis and metastasis and therapy resistance in cancer . C‐X‐C Motif Ligand 1 (CXCL1) belongs to the chemotactic superfamily and is proven to be highly expressed in several types of cancers, including melanoma, gastric cancer, and bladder cancer . CXCL1 is reported to be significantly elevated in colorectal cancer and is closely associated with tumor size, depth of the invasion, grade, and overall survival .…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8] C-X-C Motif Ligand 1 (CXCL1) belongs to the chemotactic superfamily and is proven to be highly expressed in several types of cancers, including melanoma, 9 gastric cancer, 10 and bladder cancer. 11 CXCL1 is reported to be significantly elevated in colorectal cancer and is closely associated with tumor size, depth of the invasion, grade, and overall survival. 12,13 Additionally, CXCL1 induces radioresistance by enhancing cellular DNA damage repair in a ROS-dependent manner in esophageal squamous cell carcinoma.…”

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confidence: 99%

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Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma

Wahafu

Zuo

et al. 2020

CNS Neurosci Ther

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Introduction Glioblastoma (GBM) is identified as a lethal malignant tumor derived from the nervous system. Despite the standard clinical strategy including maximum surgical resection, temozolomide (TMZ) chemotherapy, and radiotherapy, the median survival of GBM patients remains <15 months. Accumulating evidence indicates that rapid‐acquired radioresistance is one of the most common reasons for GBM recurrence. Therefore, developing novel therapeutic targets for radioresistant GBM could yield long‐term cures. Aims To investigate the functional role of CXCL1 in the acquired radioresistance and identify the molecular pathway correlated to CXCL1. Results In this study, we identified that CXCL1 is highly expressed in GBM and the elevation of CXCL1 is involved in radioresistance and poor prognosis in GBM patients. Additionally, silencing CXCL1 attenuated the proliferation and radioresistance of GBM cells. Furthermore, we demonstrated that CXCL1‐overexpression induced radioresistance through mesenchymal transition of GBM via the activation of nuclear factor‐kappa B (NF‐κB) signaling. Conclusion CXCL1 was highly enriched in GBM and positively correlated with poor prognosis in GBM patients. Additionally, elevated CXCL1 induced radioresistance in GBM through regulation of NF‐κB signaling by promoting mesenchymal transition in GBM.

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CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer

Cited by 178 publications

References 43 publications

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma

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