Estradiol Effects on Polymorphonuclear Cell Production and Actions Contribute to Estrogen-Mediated Lymphangioleiomyomatosis (LAM) Progression

Abstract

The estrogen sensitivity of Lymphangioleiomyomatosis (LAM)—a rare lung disease involving the slow growth of smooth muscle-like adenomas that result in cystic change in the lung parenchyma—is traditionally examined to assess the direct effects of estradiol on the tumor cells. However, we have observed that the estrogen sensitivity of in vitro models is markedly less pronounced than that of in vivo models, suggesting that estradiol may act elsewhere to promote tumor progression. We have previously reported that polymorphonuclear cells (PMNs) are preferentially increased in the immune microenvironment and regulate growth of LAM-like TSC2-null uterine tumors. We hypothesized that, in addition to direct effects of estrogen on tumor cells, estrogen might also stimulate tumor growth by promoting PMN production in the bone marrow and actions in the tumor microenvironment. Here, we show that estrogen availability influences the levels of PMNs in naïve and tumor-burdened mice. Using bone marrow cultures and CFC assay, we demonstrate that estradiol is a potent inducer of PMN production in chronic inflammatory conditions. Employing both pharmacologic agents and estrogen receptor (ER)-null bone marrow, we showed that ER□ is necessary for promoting a PMN fate for myeloid progenitors. While we see that the migratory, invasive, and proliferative capacities of TSC2-null cell lines are not augmented when stimulated with E2 directly, evidence shows estrogen promotes the pro-tumorigenic function of PMNs co-cultured with TSC2-null cell lines. These data provide insight into the robust effect of in vivoestrogen stimulation as estradiol may be a dual effector in LAM tumor progression and great target for anti-LAM therapeutic strategy. Supported by grants from NIH (R01CA193583, F31 CA254132-01).