Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Endocrinology. 2023 Apr 17;164(6). doi: 10.1210/endocr/bqad061.
Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by smooth muscle cell-like tumors containing tuberous sclerosis (TSC) gene mutations and found almost exclusively in females. Patient studies suggest LAM progression is estrogen dependent, an observation supported by in vivo mouse models. However, in vitro data using TSC-null cell lines demonstrate modest estradiol (E2) responses, suggesting E2 effects in vivo may involve pathways independent of direct tumor stimulation. We previously reported tumor-dependent neutrophil expansion and promotion of TSC2-null tumor growth in an E2-sensitive LAM mouse model. We therefore hypothesized that E2 stimulates tumor growth in part by promoting neutrophil production. Here we report that E2-enhanced lung colonization of TSC2-null cells is indeed dependent on neutrophils. We demonstrate that E2 induces granulopoiesis via estrogen receptor α in male and female bone marrow cultures. With our novel TSC2-null mouse myometrial cell line, we show that factors released from these cells drive E2-sensitive neutrophil production. Last, we analyzed single-cell RNA sequencing data from LAM patients and demonstrate the presence of tumor-activated neutrophils. Our data suggest a powerful positive feedback loop whereby E2 and tumor factors induce neutrophil expansion, which in turn intensifies tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth.
淋巴管平滑肌瘤病（LAM）是一种罕见的囊性肺疾病，由平滑肌细胞样肿瘤引起，这些肿瘤含有结节性硬化症（TSC）基因突变，几乎仅发生在女性中。患者研究表明，LAM 的进展依赖于雌激素，这一观察结果得到了体内小鼠模型的支持。然而，使用 TSC 缺失细胞系的体外数据表明，雌二醇（E2）的反应较为温和，这表明 E2 在体内的作用可能涉及与直接肿瘤刺激无关的途径。我们之前曾报道过，在一种雌激素敏感的 LAM 小鼠模型中，肿瘤依赖性中性粒细胞扩增和 TSC2 缺失肿瘤生长的促进作用。因此，我们假设 E2 通过促进中性粒细胞的产生来刺激肿瘤生长。在这里，我们报告称，E2 确实通过促进中性粒细胞的产生来增强 TSC2 缺失细胞对肺部的定植。我们证明 E2 通过雄性和雌性骨髓培养物中的雌激素受体 α 诱导粒细胞生成。通过我们新的 TSC2 缺失小鼠子宫平滑肌细胞系，我们表明这些细胞释放的因子可驱动 E2 敏感的中性粒细胞产生。最后，我们分析了 LAM 患者的单细胞 RNA 测序数据，并证明了肿瘤激活的中性粒细胞的存在。我们的数据表明，存在一个强大的正反馈回路，其中 E2 和肿瘤因子诱导中性粒细胞扩增，而中性粒细胞反过来又加剧肿瘤生长和产生中性粒细胞刺激因子，导致 TSC2 缺失肿瘤持续生长。
