The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance

Miękus, Katarzyna

doi:10.3892/or.2016.5297

Cited by 18 publications

(16 citation statements)

References 115 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intriguingly, in TGCT patients, an inverse correlation between progression-free survival and some circulating cytokines, including HGF, has been recently found [ 42 ]. In this respect, it is worth mentioning that c-MET availability has also been correlated with resistance to radio- and chemotherapy in different cancer types [ 43 – 45 ]. Altogether, these observations lead us to hypothesize that the deregulation of c-MET activation could represent one of the molecular mechanism responsible for the TGCT onset and/or progression.…”

Section: Introductionmentioning

confidence: 99%

c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors

et al. 2018

View full text Add to dashboard Cite

Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20–40 years). Even if diagnosed with disseminated disease, >80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and non-seminomas is due to a combination of genetic, epigenetic and microenvironment-based alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma.

show abstract

Section: Introductionmentioning

confidence: 99%

c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Moreover, CSCs have high drug resistance and antiapoptotic properties, which potentially enable them to survive clinical chemotherapies. Because CSCs induce the activation of oncogenic pathways to escape from targeted therapies through the overexpression of specific oncogenes, we hypothesized that CSCs can also contribute to immune escape through the expression of highly inhibitory proteins such as PD‐L1 against CD8+ T cells . To test this hypothesis, the molecular mechanism of PD‐L1 in EGFR‐posiitve cancers‐derived CSCs was investigated, and the inhibitory agents against the driver genes were applied to reduce the expression of PD‐L1.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Cheng¹,

Lin

Tsai³

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.

show abstract

“…To the best of our knowledge, CSCs present high drug resistance [ 7 , 8 ] and antiapoptosis property [ 9 , 10 ] to survive tumor chemotherapies. Furthermore, CSCs induce the activation of oncogenic pathways, such as MET, HER2, and Wnt, for escaping the targeted therapies [ 11 – 15 ]. Therefore, to develop an effective therapy targeting specific driver genes, investigating the molecular mechanism of CSCs is essential [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening

Cheng

Liao

et al. 2018

J Biomed Sci

View full text Add to dashboard Cite

BackgroundCancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes.MethodsIn this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs.ResultsRNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades.ConclusionsWe identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0456-y) contains supplementary material, which is available to authorized users.

show abstract

The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance

Cited by 18 publications

References 115 publications

c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors

c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening

Contact Info

Product

Resources

About