Analysis of steroid hormone effects on xenografted human NF1 tumor Schwann cells

The neurofibroma, a common feature of neurofibromatosis type 1 (NF1), is a benign peripheral nerve sheath tumor that contains predominantly Schwann cells (SC). There are reports that neurofibroma growth may be affected by hormonal changes, particularly in puberty and pregnancy, suggesting an influence by steroid hormones. This study examined the effects of estrogen and progesterone on proliferation and apoptosis in a panel of NF1 tumor xenografts. SC-enriched cultures derived from three human NF1 tumor types [dermal neurofibroma, plexiform neurofibroma and malignant peripheral nerve sheath tumor (MPNST)] were xenografted in sciatic nerves of ovariectomized scid/Nf1−/+ mice. At the same time, mice were implanted with time-release pellets for systemic delivery of progesterone, estrogen or placebo. Proliferation and apoptosis by the xenografted SC were examined two months after implantation, by Ki67 immunolabeling and TUNEL. Estrogen was found to increase the growth of all three MPNST xenografts. Progesterone was associated with increased growth in two of the three MPNSTs, yet decreased growth of the other. Of the four dermal neurofibroma xenografts tested, estrogen caused a statistically significant growth increase in one and progesterone did in another. Of the four plexiform neurofibroma SC xenografts, estrogen and progesterone significantly decreased growth in one of the xenografts, but not the other three. No relationship of patient age or gender to steroid response was observed. These findings indicate that human NF1 Schwann cells derived from some tumors show increased proliferation or decreased apoptosis in response to particular steroid hormones in a mouse xenograft model. This suggests that antiestrogen or anti-progesterone therapies may be worth considering for specific NF1 neurofibromas and MPNSTs

Potentiation of EDHF-mediated relaxation by chloride channel blockers

Aim: To investigate the involvement of Cl channels in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in rat mesenteric arteries. Methods: Cl channel and K ir channel activities were studied using whole-cell patch clamping in rat mesenteric arterial smooth muscle cells. Isometric tension of arterial rings was measured in organ chambers. Results: The volume-activated Cl current in rat mesenteric arterial smooth muscle cells was abolished by Cl channel blockers NPPB or DIDS. The EDHF-mediated vasorelaxation was potentiated by NPPB and DIDS. The EDHF response was diminished by a combination of apamin and charybdotoxin, which agreed with the hypothesis that EDHF response involves the release of K + via the Ca 2+-activated K + channels in endothelial cells. The elevation of K + concentration in bathing solution from 1.2 mmol/L to 11.2 mmol/L induced an arterial relaxation, which was abolished by the combination of BaCl 2 and ouabain. It is consistent to the hypothesis that K + activates K + /Na +-ATPase and inward rectifier K + (K ir) channels, leading to the hyperpolarization and relaxation of vascular smooth muscle. The K +-induced relaxation was augmented by NPPB, DIDS, or withdrawal of Cl from the bathing solution, which could be reversed by BaCl 2, but not ouabain. The potentiating effect of Cl channel blockers on K +-induced relaxation was probably due to the interaction between Cl channels and K ir channels. Moreover, the K +-induced relaxation was potentiated when the arteries were incubated in hyperosmotic solution, which is known to inhibit volume-activated Cl channels.Conclusion:The inhibition of Cl channels, particularly the volume-activated Cl channels, may potentiate the EDHF-induced vasorelaxation through the K ir channels. © 2010 CPS and SIMM All rights reserved.link_to_subscribed_fulltex