Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

Zhao, Zhiwei; Wang, Qianqian; Lin, Yingbo; Miao, Yong; Zeng, Ye; Nie, Yongzhan; Guo, Peng; Jiang, Guangyao; Wu, Jiang

doi:10.3892/ol.2017.6034

Cited by 31 publications

(24 citation statements)

References 114 publications

(138 reference statements)

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“…Moreover, IL-8 is an established factor that drives epithelial to mesenchymal transition in cancer cells ( 93 ). In the literature, there is a strong correlation between high expression of IL-8 and mesenchymal and stem cell features in tumor cells known for their aggressive behavior ( 94 , 95 ). Furthermore, treatment with conditioned media from cells secreting high levels of IL-8 induces epithelial-mesenchymal transition (EMT) in naive cells, while on the other hand, application of an IL-8 inhibitor leads to loss of mesenchymal markers and development of an epithelial phenotype ( 93 ).…”

Section: Non-cell Autonomous Contributions Of the Sasp To Senescencementioning

confidence: 99%

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

et al. 2018

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In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS) might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP) is a hallmark of TIS and may contribute to aberrant effects of cancer therapy. Here, we propose that the SASP may also serve as a major driver of escape from senescence and the re-emergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the restoration of tumor growth in a non-cell autonomous fashion. Accordingly, anti-SASP therapies might serve to mitigate the deleterious outcomes of TIS. In addition to providing an overview of the putative actions of the SASP, we discuss recent efforts to identify and eliminate senescent tumor cells.

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Section: Non-cell Autonomous Contributions Of the Sasp To Senescencementioning

confidence: 99%

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

et al. 2018

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“…We found that only IL‐8 was positively correlated with weight loss in cachectic patients ( P = 0.044; r = 0.627), and this cytokine was also associated with the tumour size ( P = 0.006; r = 0.760). The literature demonstrated that enhanced expression of IL‐8 is associated with cachexia progression in pancreatic cancer and with induction of fibrosis in several types of tumours …”

Section: Resultsmentioning

confidence: 99%

“…The literature demonstrated that enhanced expression of IL-8 is associated with cachexia progression in pancreatic cancer 42 and with induction of fibrosis in several types of tumours. 36,43…”

Section: Inflammatory Cytokines and Growth Factors May Contribute To mentioning

confidence: 99%

“…In addition, TGF-β contributes to EMT, 31,32 regulation of gut microbiota, 33 and angiogenesis by a reciprocal regulatory loop with secreted protein acidic and rich in cysteine (SPARC), 34,35 which is also involved in neo-angiogenesis. 36 Interestingly, high levels of TGF-β are associated with the proportion of tumour-immune infiltrating cells, as mediated by p38 mitogen-activated protein kinase (MAPK) signalling, what represents a novel putative mechanism for immune tolerance. 37 However, it remains unclear whether the tumourassociated inflammatory micro-environment contributes to fibrosis in cachectic patients.…”

Section: Introductionmentioning

confidence: 99%

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Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

Lima

Simoes

Castro

et al. 2019

J cachexia sarcopenia muscle

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Background Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. Results Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight‐stable counterparts. Also, IL‐8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α‐smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)‐β1, TGF‐β2, and TGF‐β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen‐activated protein kinase alteration. Hypoxia‐inducible factor‐1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight‐stable group (P = 0.005). Conclusions Our results demonstrate TGF‐β pathway activation in the tumour in cachexia, through the (non‐canonical) mitogen‐activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF‐β‐induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

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“…It is possible that when treating bladder cancer patients with BCG, parallel protective machineries are activated that could hinder the cancer eradication process and explain why some patients fail to respond to BCG. One such parallel process might be the secretion of IL‐8, which can act as a tumorigenic and pro‐angiogenic factor, driving tumor growth (Singh and Lokeshwar, ; Xie, ; Zhao et al ., ).…”

Section: Discussionmentioning

confidence: 97%

BCG‐induced cytokine release in bladder cancer cells is regulated by Ca²⁺ signaling

et al. 2018

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Bacillus Calmette–Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL‐8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll‐like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL‐8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

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Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

Cited by 31 publications

References 114 publications

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

BCG‐induced cytokine release in bladder cancer cells is regulated by Ca²⁺ signaling

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Epithelial-mesenchymal transition in cancer: Role of the IL-8/IL-8R axis

Cited by 31 publications

References 114 publications

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

BCG‐induced cytokine release in bladder cancer cells is regulated by Ca2+ signaling

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BCG‐induced cytokine release in bladder cancer cells is regulated by Ca²⁺ signaling