Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy

Khazali, Ahmad Suhail; Clark, Amanda M.; Wells, Alan

doi:10.1038/bjc.2017.414

Cited by 70 publications

(59 citation statements)

References 42 publications

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“…8,39 Initial studies suggest that stressors of the microenvironment, whether inflammatory cytokines or immune activators, can induce cEMT even in well-differentiated carcinoma cells. [40][41][42][43] This is supported by our finding that stressed endothelial cells activated a emergent or mesenchymal phenotypic shift in an E-cadherin-expressing breast carcinoma cell line via secreted growth factor, 40 and work by others implicating a role for endothelium undergoing sprouting as driving tumor emergence. 34 Additional signals can derive from activated stellate cells and macrophages to promote this same shift.…”

Section: The Metastatic Cascadesupporting

confidence: 57%

The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

Wells

Clark

Bradshaw

et al. 2018

Exp Biol Med (Maywood)

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Cancer mortality ensues from metastatic growths. Cancers use two strategies to allow for this unrelenting expansion. The first way is that early metastases are often cryptic or dormant, being invisible to both innate suppressive actions and undetected clinically. Second, both the micrometastases and later clinically lethal growths are resistant to therapies, whether standard chemotherapies, targeted biologics, or even immunotherapies. These two modes of resistance necessitate new approaches to treatments if we are to eliminate mortality from solid tumors. However, to develop such therapeutic strategies, we first need to better understand the cellular behaviors and molecular events that enable the resistances. Herein, we present a comprehensive model of changing methods of avoidance and resistance that occur during tumor progression, and doubly confound treatment by mixing survival strategies throughout the continuum creating moving targets. Melanoma is presented as the model cancer, as it is being targeted by all three types of agents for disseminated disease, with breast and prostate cancer as two other key carcinomas. Impact statement Cancers kill mainly because metastatic disease is resistant to systemic therapies. It was hoped that newer targeted and immunomodulatory interventions could overcome these issues. However, recent findings point to a generalized resistance to elimination imparted by both cancer-intrinsic and -extrinsic changes to provide survival advantages to the disseminated tumor cells. Here, we present a novel conceptual framework for the microenvironmental inputs and changes that contribute to this generalized therapeutic resistance. In addition we address the issues of experimental systems in terms of studying this phenomenon with their advantages and limitations. This is meant to spur studies into this critical aspect of tumor progression that directly leads to cancer mortality.

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Section: The Metastatic Cascadesupporting

confidence: 57%

The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

Wells

Clark

Bradshaw

et al. 2018

Exp Biol Med (Maywood)

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“…Anti-cancer therapies promote entry into dormancy, and the local microenvironment seems to be a critical endogenous determinant for entry into and exit from dormancy [41]. In fact, chemokines as inflammatory mediators affect cancer dormancy [42][43][44]. Distinct chemokines, in particular CXCL12, CXCL16, and CX3CL, are essential for tumor preservation with their autocrine or paracrine signaling promoting anti-apoptotic effects or proliferation of many tumor types including GBMs [27][28][29][30][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the impact of cyto-and chemokines on dormancy-related pathways has been partly studied in other tumors. De Cock et al [46] showed that inflammation triggered the escape of metastatic breast cancer cells from a dormant phase, and two other studies demonstrated that the recovery of dormant breast cancer cells depended on IL-6, IL-8, and TGF-ß1 signaling [43,47]. Further, downregulation of CXCR4 in metastatic breast cancer cells was linked to restrained proliferation [44].…”

Section: Discussionmentioning

confidence: 99%

Entry and exit of chemotherapeutically-promoted cellular dormancy in glioblastoma cells is differentially affected by the chemokines CXCL12, CXCL16, and CX3CL1

et al. 2020

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Glioblastoma multiforme (GBM) is a malignant brain tumor that evades therapy regimens. Since cellular dormancy is one strategy for surviving, and since chemokines determine the environmental conditions in which dormancy occurs, we investigated how chemokines affect temozolomide (TMZ)-promoted cellular dormancy entry and exit in GBM cells. TMZ administration over ten days promoted cellular dormancy entry, whereas discontinuing TMZ for a further 15 days resulted in resumption of proliferation. Co-administration of a chemokine cocktail containing CXCL12, CXCL16, and CX3CL1 resulted in both delayed entry and exit from cellular dormancy. A microarray-based transcriptome analysis in LN229 GBM cells revealed that cellular dormancy entry was characterized by an increased expression of CCL2 and SAA2, while THSD4, FSTL3, and VEGFC were upregulated during dormancy exit. Co-stimulation with the chemokine cocktail reduced upregulation of identified genes. After verifying the appearance of identified genes in human GBM primary cultures and ex vivo samples, we clarified whether each chemokine alone impacts cellular dormancy mechanisms using specific antagonists and selective CRISPR/Cas9 clones. While expression of CCL2 and SAA2 in LN229 cells was altered by the CXCL12-CXCR4-CXCR7 axis, CXCL16 and CX3CL1 contributed to reduced upregulation of THSD4 and, to a weaker extent, of VEGFC. The influence on FSTL3 expression depended on the entire chemokine cocktail. Effects of chemokines on dormancy entry and exit-associated genes were detectable in human GBM primary cells, too, even if in a more complex, cell-specific manner. Thus, chemokines play a significant role in the regulation of TMZ-promoted cellular dormancy in GBMs.

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“…It is believed that the influence of MSCs on can- cer cells (including immune suppression) may be mediated via cell secrotome (immune-effective ILs and their signalization cascades) and exosomes in which contain miRNAs and/or mitochondria or via tight junctions between cells 23) . For instance, IL-1β has critical results on all three mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation 24) that have suppressor effects in the early stages of cancers, although some activating roles on advanced cancers have been also reported 25) , the same features being described for TGF-β 26) and for IL-8 via extracellular-signal-regulated kinase (ERK) signaling 27) . Also, IL-1β, IL-6, and the vascular cell adhesion molecule 1 (VCAM-1) aid circulating tumor cells to cluster with neutrophils 28) .…”

Section: Stem Cells Growth Factors and Interleukinsmentioning

confidence: 96%

Exploring the Role of Stem Cells in Cancer Development and Progression

Ebrahimi

Abbasi

Cucchiarini

2020

Ann. Cancer Res. Therap.

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Tumors comprise two types of non-cancerous cells, first recruited cells such as stem cells and macrophages, and second, tissue-steady cells that are part of the tissue including adipose cells, fibroblasts, and steady macrophage-derived cells, all having a significant impact on tumor progression. This review addresses some effects of stem cells on cancer advancement as the predominant outcome of stem cell therapy on cancer cell lines revealed controversial results. In addition, this review will address some reasons of distinct cancer responses and hypotheses the notion of unfolded protein response as a key switch in cancer development.

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Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy

Abstract: Activated stellate cells can induce breast cancer emergence from dormancy in the liver by secreting inflammatory cytokines. Preventing liver inflammation or disrupting the subsequent key cytokines may prevent metastatic outgrowth.

Cited by 70 publications

References 42 publications

The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

Entry and exit of chemotherapeutically-promoted cellular dormancy in glioblastoma cells is differentially affected by the chemokines CXCL12, CXCL16, and CX3CL1

Exploring the Role of Stem Cells in Cancer Development and Progression

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