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Abstract
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 anti-estrogen or anti-progesterone therapies may be worth considering for specific NF1 neurofibromas and MPNSTs.
Acknowledgements
This work was supported by US Department of Defense NF Research Program grants [M.R.W. (170110707), D.M. (170010549)], an NIH NRSA fellowship (L.F., 1F30NS43951) and the Hayward Foundation (M.R.W.). We thank Debbie Neubauer and Beth Fisher for technical assistance.
Figures and Tables
Figure 1 Representative sNF96.2 xenograft whole sciatic nerves show visible additional growth under influence of estrogen. The leftmost nerve is from a mouse treated with estrogen. The middle nerve is from a mouse treated with placebo pellet. The rightmost nerve is from an untreated mouse, where the nerve was injected with PBS as injection control.
Figure 2 Cultured plexiform pNF01.1 Schwann cells are shown, stained with S-100, at x40 magnification. This culture shows characteristic enrichment for SC.
Figure 3 Immunohistochemical staining of plexiform pNF95.11b xenograft with progesterone hormone treatment. (A) H/E stain. (B) hGST immunostain (brown cells are engrafted human SC). (C) Ki-67 immunostain for proliferation. (D) TUNEL stain for apoptosis. Magnification x200.
Figure 4 (A) Effect of hormones on xenograft compared to placebo. The star indicates p ≤ 0.05. Open bar, placebo; gray bar, estrogen; black bar, progesterone. Xenografts of sNF94.3 and cNF97.5 showed statistically significant increase in response to estrogen, whereas the pNF95.11b xenograft showed significant inhibition with both hormones, compared to placebo. Progesterone was associated with an increase in the cNF99.1 xenograft. (B) Xenograft of sNF96.2 showed statistically significant inhibition in response to progesterone, but increase in xenograft size in response to estrogen.
Figure 5 Example of hormone effects on xenografts at a gross morphology level. Photomicrographs are shown for the dermal neurofibroma cNF97.5 xenograft immunostained with hGST antibody to show cells of human origin. Photos (A and D) are placebo sections from left side and right side nerves, respectively; (B and E) are estrogen-associated sections; (C and F) are progesterone-associated sections. An increase in xenograft size can be seen in the presence of estrogen, but not progesterone. The magnification is x200.
Figure 6 Comparison of the effects of hormone on sNF96.2 xenograft in Nf1+/−, scid mice versus Nf1+/+, scid mice. The star * indicates statistically significant results with p ≤ 0.05. Gray bar, Nf1+/−; black bar, Nf1+/+.
