The Involvement of Angiotensin Type 1 and Type 2 Receptors in Estrogen-Induced Cell Proliferation and Vascular Endothelial Growth Factor Expression in the Rat Anterior Pituitary

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary

Interferon alpha and rapamycin inhibit the growth of pheochromocytoma PC12 line in vitro

Wstęp: Guzy chromochłonne (pheochromocytoma/paraganglioma) należą do łagodnych lub złośliwych nowotworów neuroendokrynnych.Wobec niezadowalającej skuteczności standardowych sposobów leczenia pacjentów z rozsianą postacią choroby, wciąż poszukuje się nowych metod terapii, w tym możliwości skutecznego leczenia celowanego. W związku ze wzmożonym unaczynieniem tych nowotworów, preparaty o działaniu antyangiogennym mogą potencjalnie stanowić nową grupę leków stosowanych w leczeniu pheochromocytoma/paraganglioma.Materiał i metody: W badaniu oceniano wpływ różnych angiomodulatorów: VEGF (naczyniowo-środbłonkowy czynnik wzrostu) orazpięciu endo- i egzogennych czynników antyangiogennych (endostatyna; IFN-alfa [interferon alfa]; rapamycyna — inhibitor szlaku mTOR[mammalian target of rapamycin]; JV1-36 and SU5416 [semaxinib]) na wzrost szczurzej linii pheochromocytoma PC12.Wyniki: IFN-alfa (105 U/mL) silnie hamował wzrost komórek PC12 w hodowli 72 h, nasilając apoptozę i hamując cykl komórkowy. Rapamycynaw szerokim zakresie stężeń (10-5 to 10-8 M) nieznacznie zmniejszała żywotność komórek PC12, a w stężeniu 10-5 M także hamowałaich proliferację. VEGF, endostatyna oraz JV1-36 nie wpływały na wzrost lini PC12.Wnioski: W badaniu po raz pierwszy wykazano, że IFN-alfa hamuje wzrost linii komórkowej pheochromocytoma PC12, a także potwierdzonohamujący wpływ rapamycyny wobec tej linii komórkowej. Uzyskane wyniki sugerują zatem, że IFN-alfa oraz inhibitory szlakumTOR mogą być potencjalnie skuteczne w leczeniu złośliwych postaci guzów chromochłonnych i zachęcają do dalszych badań w tymkierunku.(Endokrynol Pol 2013; 64 (5): 368–374)Introduction: Pheochromocytomas are benign or malignant neuroendocrine tumours. The unsatisfactory efficacy of the traditionaltherapeutic methods for patients with metastatic disease results in a continuing search for more effective and targeted agents. Due to theincreased vascularisation of these tumours, inhibitors of angiogenesis could be potentially a new group of drugs in pheochromocytoma/paraganglioma therapy.Material and methods: The aim of this study was to evaluate the influence of angiomodulators: VEGF (vascular endothelial growth factor)and five endogenous and exogenous antiangiogenic compounds (endostatin; IFN-alpha [interferon alpha]; rapamycin — mTOR [mammaliantarget of rapamycin] inhibitor; JV1-36 and SU5416 (semaxinib]) on the growth of rat pheochromocytoma PC12 cell line.Results: IFN-alpha (105 U/mL) strongly inhibited PC12 growth in a 72 h culture, increasing apoptosis and arresting the cell cycle. Rapamycinin a wide range of concentrations (10-5 to 10-8 M) induced a slight inhibitory effect on PC12 viability and decreased cell proliferation at theconcentration of 10-5 M. VEGF, endostatin and JV1-36 did not influence the growth of PC12.onclusions: The study has shown for the first time that IFN-a inhibited the growth of pheochromocytoma PC12 line and confirmed theinhibitory action of rapamycin on these cells. The results suggest that IFN-alpha and mTOR inhibitors could be potentially effective in thetherapy of malignant pheochromocytoma, and encourage further study in this field.(Endokrynol Pol 2013; 64 (5): 368–374

Elevated Peripheral Blood Plasma Concentrations of Tie-2 and Angiopoietin 2 in Patients with Neuroendocrine Tumors

Background: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. Methods: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. Results: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. Conclusions: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases

Angiotensins Inhibit Cell Growth in GH3 Lactosomatotroph Pituitary Tumor Cell Culture: A Possible Involvement of the p44/42 and p38 MAPK Pathways

The local renin-angiotensin system is present in the pituitary. We investigated the effects of angiotensins on GH3 lactosomatotroph cells proliferation in vitro and the involvement of p44/42 and p38 MAPK inhibitors in the growth-regulatory effects of angiotensins. Materials and Methods. Cell viability using the Mosmann method and proliferation by the measurement of BrdU incorporation during DNA synthesis were estimated. Results. Ang II and ang IV decreased the viability and proliferation of GH3 cells. Inhibitor of p44/42 MAPK attenuated the effects of ang II on cell viability and proliferation but did not affect the ang 5-8-dependent actions. Inhibitor of p38 MAPK prevented the decrease in the number of GH3 cells in ang-II- and ang-IV-treated groups. Conclusions. The growth-inhibitory effect of ang II is possibly mediated by the p44/42 MAPK. The p38 MAPK appears to mediate the inhibitory effects of both ang II and ang 5–8 upon cell survival

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery