Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia

Vijay, Vindhya; Miller, Regan; Vue, Gau Shoua; Pezeshkian, Mida Bahareh; Maywood, Michael; Ast, Allison; Drusbosky, Leylah; Pompeu, Y.A.; Salgado, Alan D.; Lipten, Samuel D.; Geddes, Timothy J.; Blenc, Ann Marie; Ostrov, David A.; Cogle, Christopher R.; Madlambayan, Gerard J.

doi:10.1016/j.leukres.2019.106180

Cited by 41 publications

(39 citation statements)

References 57 publications

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“…In a first attempt to identify downstream mediators of CGRP-CALCRL signaling in AML, the cytokine secretome of HNT-34 cells exposed to CGRP for various periods of time was determined (Figure S6). Among others, CGRP stimulated the secretion of IL-8, which also has been implicated in chemotherapy resistance in AML and may represent an alternative druggable target [52].…”

Section: Discussionmentioning

confidence: 99%

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Gluexam

Grandits

Schlerka

et al. 2019

IJMS

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The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.

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Section: Discussionmentioning

confidence: 99%

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Gluexam

Grandits

Schlerka

et al. 2019

IJMS

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“…In line with this notion, it has been demonstrated that IL8 is a hypoxia-regulated cytokine that promotes migration in mesenchymal stromal cells in the BM 38 and that both endogenous and hypoxia-induced production of IL8 was higher in AML cases compared to controls and was prognostically unfavourable 38 . A more recent study has also suggested that IL8 blockade might be used as new therapeutic strategy for AML, as it prevents activated endothelial cell mediated proliferation and chemoresistance 39 .…”

Section: Discussionmentioning

confidence: 99%

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

et al. 2020

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The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13 rs1295686A/A genotype had an increased risk of AML (P Corr = 0.0144) whereas carriers of the VEGFA rs25648T allele had a decreased risk of developing the disease (P Corr = 0.00086). In addition, we found an association of the IL8 rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (P Corr = 0.072). Functional experiments suggested that the effect of the IL13 rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8 rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

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“…Swarnali Acharyya et al first described that endothelial cells were involved in the development of chemoresistance of breast cancer via secretion of TNF-a (12). Increasing evidence has demonstrated that endothelial cells contribute to chemoresistance of cancer cells by secreting soluble factors in a paracrine fashion in lymphoma (13)(14)(15), glioblastoma (16,17), colorectal cancer (18,19), and other cancer types (20)(21)(22)(23). Results from these studies showed that secreted factors including exosomes from endothelial cells can activate "cancer-advancing" signaling pathways in cancer cells such as AKT, Wnt, NOTCH, and epithelial-mesenchymal transition pathways in favor of survival under chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway

Zhou

Zhang

et al. 2020

Front. Oncol.

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Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer. However, little attention has been paid to the role of endothelial cells in the development of docetaxel resistance in prostate cancer. Here, we sought to investigate the function and mechanism of endothelial cells involving in the docetaxel resistance of prostate cancer. We found that endothelial cells significantly promoted the proliferation of prostate cancer cells and decreased their sensitivity to docetaxel. Mechanistically, basic fibroblast growth factor (FGF2) secreted by endothelial cells leads to the upregulation of ETS related gene (ERG) expression and activation of the Akt/mTOR signaling pathway in prostate cancer cells to promote docetaxel resistance. In summary, these findings demonstrate a microenvironment-dependent mechanism mediating chemoresistance of prostate cancer and suggest that targeting FGF/FGFR signaling might represent a promising therapeutic strategy to overcome docetaxel resistance.

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Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia

Cited by 41 publications

References 57 publications

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway

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