The New Molecular Targets Of Adrenal Malignant Tumor

Objective: To investigate whether the expression of heat shock protein 90(HSP90) is associated with the malignant pheochromocytoma(PHEO) and the effects of 17-allylamino-17-demethoxygeldanamcyin(17-AAG) and Ganetespib in PHEO cell line PC12 and in a xenograft mouse model. Methods: The expression of HSP90 was investigated in paraffin-embedded samples of PHEO patients using immunohistochemistry. The time and concentration effects of 17-AAG and Ganetespib were investigated in PHEO PC12 cells. Cell proliferation was measured by MTT assay and cell counting. Apoptosis was detected by flow cytometry. Results: HSP90 inhibitors inhibited the proliferation of HCC cells in a time- and concentration-dependent manner. The apoptosis rates of PC12 cells after treatment with HSP90 inhibitors were significantly higher than that in blank control group. Treatment with HSP90 inhibitors induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Furthermore, HSP90 inhibitors also signicantly inhibited the expression of HSP90 and its client proteins. Conclusions: Our results validated HSP90 as an important target in pheochromocytoma and provided rationale for the testing of HSP90 inhibitors as a promising therapeutic agent in the antitumor therapy of pheochromocytoma.Objective To investigate the curative effect of mammalian target of rapamycin(m TOR) inhibitor everolimus on the malignant pheochromocytoma xenograft in nude mice, and to explore the possible mechanism of everolimus on the tumor growth and angiogenesis of malignant pheochromocytoma. Methods The malignant pheochromocytoma xenograft model was created by implanting PCI2 cells in the left flank of nude mice. After 15 days, the nude mice were randomly divided into two groups: the experiment group(receiving everolimus by gavage at a dose of 5mg/kg) and the control group(treated with NS by gavage at a dose of 10 m L/kg). After 3 weeks’ treatment, the tumors were obtained, and the tumor volumes were measured in the 4th week. During this time, the changes of tumor volumes were observed and the survival time was recorded. The expressions of signal transducers and activators of transcription 3(STAT3) and vascular endothelial growth factor(VEGF) were detected by immunohistochemical staining and Western blotting. Results In the 4th week, the tumor size in the experiment group was(1506.01-5352.69) mm2, while that in the control group was(4 340.67±794.07) mm3. The growth of tumor in the experiment group was slower than that in the control group, which had a statistical significance. The average survival time of the experiment group was(37.8±4.6)days, while that in control group was(25.3± 2.4)days, with statistical significance in these data.The expressions of STAT3 and VEGF of tumor issues in the experiment group were significantly lower than those in the control group(P<0.05). Conclusions Everolimus has a significant effect on the transplanted pheochromocytoma in nude mice and suppresses the expression of STAT3 and VEGF in the tumor tissues. Aims The aim of this study was to determine the correlation between human adrenocortical carcinoma(ACC) and the proteins involved in tumor angiogenesis, and to evaluate the angiogenic status of ACC. Methods The expression of signal transducer and activator of transcription 3(STAT3) and insulin-like growth factor 2(IGF2) as well as microvessel density(MVD) were measured in a series of tissue samples from 46 human sporadic adrenocortical tumors by immunohistochemistry. These specimens were classified as adenomas(n=22) and carcinomas(n=24) according to the histological criteria defined by Weiss. Results A total of 19 of 24(79.17%) malignant cases showed positive staining for STAT3 and 4 of 20(20.00%) benign cases showed positive, the difference of STAT3 expression between ACA and ACC was statistically significant(P<0.001). Similarly, IGF2 staining was seen in 70.83%(17/24) of the malignant cases versus 25.00%(5/20) of the benign, the difference of IGF2 expression among two groups was statistically significant(P=0.002). Malignant cases showed higher MVD compared to benign tumors(84.70±12.44 VS 21.05±8.07, P<0.001). STAT3 and IGF2 expression were positively correlated with MVD in all specimens(r_s=0.832, P=0.010; r_s=0.703, P<0.001). Conclusions This study has confirmed that ACC overexpress STAT3 and IGF2, these results suggest that angiogenesis of human ACC maybe mediated by these proteins and they could represent selective targets for the molecularly targeted treatments of ACC.