Tumour Biol. 2006;27(3):153-7.
Epub 2006 Apr 11. Clin Otolaryngol. 2006
Expression of tyrosine kinase receptors in lung carcinoids.
Granberg D, Wilander E, Oberg K.
Department of Endocrine Oncology,
OBJECTIVES: Typical lung carcinoids are usually relatively benign tumors, but distant metastases are seen in up to 12% of the patients. In contrast, atypical carcinoids are more aggressive tumors, displaying metastases in up to 70%. The current treatment of metastatic lung carcinoids is discouraging. New therapies, such as inhibitors of the tyrosine kinase receptor family c-kit, platelet-derived growth factor receptors (PDGFR) alpha and beta and epidermal growth factor receptor (EGFR) have shown promising results in other malignancies and might be of value in malignant lung carcinoids. PATIENTS AND METHODS: Tumor tissue from 51 patients with typical lung carcinoids were immunostained with polyclonal antibodies against c-kit, PDGFRalpha, PDGFRbeta and EGFR. Of the 24 patients who had metastatic disease, 17 had distant metastases. Fifteen of the patients had died from their disease. RESULTS: Twelve of the tumors stained positive for c-kit, 44 expressed PDGFRalpha, 30 showed positive immunoreactivity for PDGFRbeta and 26 were EGFR immunoreactive. Among the 17 patients with distant metastases, 5 tumors expressed c-kit, 12 were PDGFRalpha immunoreactive, 9 stained positive for PDGFRbeta, and 7 showed positive immunoreactivity for EGFR. There was no correlation to distant metastases or survival for c-kit, PDGFRbeta or EGFR. CONCLUSIONS: Tyrosine kinase receptors such as c-kit, PDGFRalpha, PDGFRbeta and EGFR are expressed in a significant number of patients with metastatic lung carcinoids. Treatment with inhibitors of the tyrosine kinase receptors expressed may be considered.
PMID: 16612146 [PubMed - indexed for MEDLINE
PTTG promotes a novel VEGF-KDR-ID3 autocrine mitogenic pathway in thyroid cancer.
Kim DS, Buchanan MA, Stratford AL, Watkinson JC, Eggo MC, Franklyn JA, McCabe CJ.
Department of ENT Surgery,
Background. VEGF exerts its effects by binding to tyrosine kinase receptors, KDR and VEGFR1. KDR is critical for transmitting signals for proliferation of endothelial cells but is also expressed in several non-endothelial cells suggesting existence of autocrine stimulatory pathways. Study-design. We investigated VEGF and KDR expression in human thyroid epithelial cells in vitro and thyroid cancers samples ex vivo. Results. Expression of KDR was demonstrated using Taqman RT-PCR and Western blotting in a human follicular thyroid cancer line (FTC133) and primary thyroid epithelial cells. Further, VEGF-specific and dose-dependent activation of KDR-dependent MAPK signalling and KDR-dependent mitogenesis was demonstrated. KDR mRNA expression was elevated in thyroid cancers (2.5-fold, n = 38, P < 0.001), and immunohistochemistry demonstrated stronger phosphorylated-KDR staining in thyroid cancer cells. Further, we showed that PTTG, an oncogene known to promote angiogenesis, up-regulates KDR (2.2-fold, P = 0.006) and VEGF (2.4-fold, P < 0.001) expression in FTC133 thyroid cells. Next, we examined expression of ID3, known to be important in VEGF-dependent angiogenesis, and VEGF mRNA expression in a series of thyroid cancers. We observed a strong positive correlation between expression of these genes (R(2) = 0.62, P < 0.001). Stimulation of FTC133 cells with exogenous VEGF increased ID3 expression (2.1-fold, P < 0.001), an effect abrogated by a KDR-specific inhibitor, suggesting VEGF regulation of ID3 is KDR-dependent. Conclusion. We suggest the presence of a VEGF-KDR-ID3 dependent autocrine pathway in thyroid cells. By up-regulating both VEGF and KDR expression, we propose that PTTG may promote this autocrine proliferative pathway which may in turn be critical to thyroid cancer progression.
PMID: 16759264 [PubMed - in process]
Tumour Biol. 2006;27(3):153-7. Epub 2006 Apr 11.
Clin Otolaryngol. 2006 Jun;31(3):246.