Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor

Dong, Gang; Lee, Tin‐Lap; Yeh, Ning T.; Geoghegan, Joel; Waes, Carter Van; Chen, Zhong

doi:10.1038/sj.onc.1207851

Cited by 56 publications

(46 citation statements)

References 40 publications

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“…Thus, the aberrant function of molecules controlling the synthesis and degradation of phosphatidylinositol 3,4,5-triphosphate, phosphatidylinositol 3 ¶-OH kinase, and PTEN may help explain the presence of activated Akt in the absence of persistent EGFR signaling. This, as well as the possibility that other overactive tyrosine kinase growth factor receptors, such as c-Met or HER2 (59,60), may result in the EGFR-independent stimulation of Akt in HNSCC, warrants further investigation. Of interest, a surprising observation in this TMA analysis was that the proportion of HNSCC cases that were positive for Akt Thr308 was smaller than that of Akt Ser473 .…”

Section: Discussionmentioning

confidence: 99%

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Molinolo

Hewitt

Amornphimoltham

et al. 2007

Clinical Cancer Research

228

200

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Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. Conclusions:These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

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Section: Discussionmentioning

confidence: 99%

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Molinolo

Hewitt

Amornphimoltham

et al. 2007

Clinical Cancer Research

228

200

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“…HGF/c-MET receptor-induced activation of the mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) signal pathways was previously shown to contribute to expression of IL-8 and VEGF by HNSCC and other cells (9,10). We also recently showed that enforced expression of HGF promoted expression of homologues Gro 1 and VEGF and angiogenesis, tumorigenesis, and metastasis of SCC overexpressing c-Met in a murine model (11). VEGF, IL-8, and Gro 1/Gro a (KC in mouse) have been shown to be key factors in mediating angiogenesis in SCC and other cancers (12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 92%

Hepatocyte Growth Factor/Scatter Factor Differentially Regulates Expression of Proangiogenic Factors through Egr-1 in Head and Neck Squamous Cell Carcinoma

et al. 2005

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Hepatocyte growth factor/scatter factor (HGF) and the angiogenesis factors platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) are found in elevated concentrations in serum or tumor tissue of patients with head and neck squamous cell carcinomas (HNSCC), suggesting these factors may be coregulated. A cDNA microarray analysis for HGF-inducible genes revealed that HGF also modulates PDGFA expression, a gene recently shown to be inducible by the transcription factor, early growth response-1 (Egr-1). In the present study, we investigated the potential role of HGF-induced Egr-1 in expression of PDGF, VEGF, and IL-8. HGF induced expression of all three factors and Egr-1 expression and DNA-binding activity. The analysis of promoter sequences showed putative Egr-1 binding sites in the PDGFA or VEGF but not in the IL-8 promoter, and HGFinduced Egr-1-binding activity was confirmed by chromatin immunoprecipitation (ChIP) assay. The maximal basal and HGF-induced promoter activity for the PDGFA gene existed within À630 bp of the promoter region, and overexpression of Egr-1 significantly increased such activity. Consistent with this, expression of PDGFA and VEGF but not IL-8 showed corresponding differences with Egr-1 expression in HNSCC tumor specimens and were strongly suppressed by transfection of Egr-1-antisense or small interference RNA (siRNA) oligonucleotides. HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways. We conclude that the HGF-induced activation of transcription factor Egr-1 by MEK1/2-and PKC-dependent mechanisms differentially contributes to expression of PDGF and VEGF, which are important angiogenesis factors and targets for HNSCC therapy. (Cancer Res 2005; 65(16): 7071-80)

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“…Certain studies have demonstrated that HGF can enhance the generation of GRO-1 and VEGF in vitro (38) and another study indicated that serum levels of HGF in head and neck squamous cell carcinoma can regulate the expression of PDGF-A (39). There were correlations between two of either GRO-1, HGF and PDGF-AA in the present study, which suggests that they have a common role in angiogenesis (11,17,40), while no association was found between sE-selectin and GRO-1 and PDGF-AA.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

Expression of growth-regulated oncogene-1, hepatocyte growth factor, platelet-derived growth factor-AA and soluble E-selectin and their association with high-risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix

Zhang

Yang

et al. 2014

Molecular Medicine Reports

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Abstract. The aim of the present study was to evaluate the clinical significance and prognostic value of growth-regulated oncogene-1 (GRO-1), hepatocyte growth factor (HGF), platelet-derived growth factor-AA (PDGF-AA), soluble E-selectin (sE-selectin) and high-risk human papillomavirus (HPV; types 16, 18/45, 31 and 33/52/58/67) infection in cervical squamous cell carcinoma (CSCC). A total of 426 cases were enrolled in the present study, of which 292 cases were patients with CSCC, 43 were patients with cervical intraepithelial neoplasia (CIN) and 91 were healthy controls. Luminex xMAP technology was used to detect the serum levels of GRO-1, HGF, PDGF-AA and sE-selectin in all cases and two-channel fluorescence quantitative polymerase chain reaction was used to determine HPV DNA in cervical scrapings from CSCC and CIN patients. The results demonstrated that the serum levels of GRO-1, HGF and sE-selectin were significantly higher in patients with CSCC compared with patients with CIN and the healthy controls (P<0.0001). Compared with the CIN patients, the HPV positive rate in the CSCC patients significantly increased (P= 0.013). The four factors were correlated with certain clinicopathological variables of CSCC patients to a certain degree (P<0.05) and the levels of HGF were closely associated with HPV infection (P= 0.039). The receiver operating characteristic curves demonstrated that HGF obtained the highest diagnostic value compared with the other three factors. Multivariate Cox regression analysis demonstrated that the serum levels of HGF (P<0.0001), FIGO stage (P<0.0001) and pelvic lymph node metastasis (P=0.001) were independent prognostic factors in patients with CSCC, while high-risk HPV infection did not show any significance in this analysis. These results demonstrated that HGF may be a useful prognostic biomarker rather than high-risk HPV types in patients with CSCC.

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Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor

Cited by 56 publications

References 40 publications

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Hepatocyte Growth Factor/Scatter Factor Differentially Regulates Expression of Proangiogenic Factors through Egr-1 in Head and Neck Squamous Cell Carcinoma

Expression of growth-regulated oncogene-1, hepatocyte growth factor, platelet-derived growth factor-AA and soluble E-selectin and their association with high-risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix

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