TLR4 signaling induces the release of microparticles by tumor cells that regulate inflammatory cytokine IL-6 of macrophages via microRNA let-7b

Li, Dapeng; Jia, Haibo; Zhang, Huafeng; Lv, Meng; Liu, Jing; Zhang, Yi; Huang, Tao; Huang, Bo

doi:10.4161/onci.19854

Cited by 46 publications

(42 citation statements)

References 35 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have demonstrated that several molecules or receptors can induce cytoskeletal remodeling. Toll-like receptor 4 induces remodeling via phosphorylation of the myosin light chain for the release of microparticles, thus regulating tumor inflammatory microenvironment (17). Goodwin et al (18) reported that, in motor neuron cells, CDK-5 regulates microtubule orientation and in cancer, Strock et al (8) reported that inhibiting the activity of CDK5 resulted in changes in the microtubule cytoskeleton, loss of cellular polarity and loss of motility in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Zhou

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Determining the molecular phenotype is a key to understanding and predicting the metastatic potential and the prognosis for patients with lung cancer. Our previous study demonstrated that increased expression of cyclin-dependent kinase 5 (CDK5) in patients with non-small cell lung cancer (NSCLC) is associated with a poorer prognosis. The present study aimed to further investigate the underlying mechanism of CDK5 in vitro and in vivo using the A549 human NSCLC cell line. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to quantify the proliferation of the A549 cells; migration assay and invasiveness assays were performed using Transwell chambers and wound healing assays were used to assess cell motility, which was assessed by measuring the movement of cells. Inhibition of CDK5 by roscovitine and small interfering (si)RNA was used to investigate the mechanism of CDK5 in the process of A549 lung cancer cell proliferation, migration and invasion. The results demonstrated that functional inhibition of CDK5 using roscovitine and siRNA markedly suppressed the proliferation of A549 cells and resulted in a reduced tumor mass in vivo. In addition, the hinhibition of CDK5 reduced the migration and invasiveness of the A549 cells in vitro and in vivo. Notably, CDK5 inhibition also impaired tumor cell cytoskeletal remodeling and led to loss of cell polarity, which may partially explain the reduction of A549 cell mobility and invasiveness.The results of the present study revealed that CDK5 may be important in the regulation of migration and invasiveness in NSCLC through its effects on cytoskeletal remodeling. IntroductionLung cancer has long been the leading cause of cancer-associated mortality worldwide (1). Although numerous therapeutic strategies have improved significantly, the presence of locally advanced or metastatic lung cancer reduces the curability of this life-threatening disease. Several efforts have been made to understand the mechanism and molecular pathogenesis of this disease, with promise in the development of more effective targeted treatment strategies for lung cancer, particularly non-small cell lung cancer (NSCLC). Certain small molecular inhibitors have been developed against certain tyrosine kinases, including epidermal growth factor receptor and vascular endothelial growth factor receptor (2); however, the overall progression free survival rate has not improved satisfactorily (3). The poor survival rate is predominantly attributed to aggressive growth, advanced stage at diagnosis and local recurrence (4). The identification of effectors, which modulate growth, cell migration and invasion will assist in understanding the process of disease progression and enable the development of novel therapeutic targets for patients with NSCLC.Cyclin-dependent kinase 5 (CDK5) has been recognized as a key factor in regulating the migration and plasticity of neuron cells (5,6). Compared with other CDKs, CDK5 is considered to be an essential regulator of neuronal differentiation, ra...

show abstract

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Zhou

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…30 Many signals are capable of inducing cytoskeletal alteration, including TLR4 signaling, commonly existed in the tumor microenvironment, that can be transduced to cellular cytoskeletons of tumor cells, leading to their releasing MPs. 31 In addition, hypoxia, nutrient deficiency and apoptotic signals also induce tumor cells to produce MPs in tumor microenvironment. In practice, both chemotherapy and radiotherapy cause abundant tumor cell death, leading to their releasing MPs.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

et al. 2017

Self Cite

View full text Add to dashboard Cite

Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumorinhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.

show abstract

“…Moreover, a variety of signal molecules in tumor microenvironment can also stimulate tumor cells to produce MPs. 16 In practice, both chemotherapy and radiotherapy can kill plenty of tumor cells, leading to the production of MPs. Therefore, the generation of tumor cellderived MPs (T-MP) might be a very common phenomenon in tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression

Chen

et al. 2016

OncoImmunology

Self Cite

105

View full text Add to dashboard Cite

Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

show abstract

TLR4 signaling induces the release of microparticles by tumor cells that regulate inflammatory cytokine IL-6 of macrophages via microRNA let-7b

Cited by 46 publications

References 35 publications

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression

Contact Info

Product

Resources

About