Estrogen Promotes Lymphangioleiomyomatosis (LAM) Indirectly Through Stimulation of Innate Immunity
Abstract
Lymphangioleiomyomatosis (LAM) is a rare lung disorder that consists of multiple smooth muscle-like tumors that progressively grow until they interfere with normal lung function. Many patients with LAM will have a lung collapse or develop fluid in their lungs, and some will require lung transplantation. Even after transplantation, many patients find that tumors return to the lungs. In addition to the suffering that accompanies the progressive suffocation due to the loss of functional lung, the ultimate fate for a large number of patients is death. The goal of the research proposed here is to find better treatments for LAM. Importantly, LAM has some unusual properties that, if better understood, could be used against it when it comes to treatment. First, LAM is found almost exclusively in women, suggesting that the LAM tumors may originate from or be stimulated by factors found primarily in women. Second, LAM tumors develop after puberty, grow more during pregnancy or on birth control pills, and stabilize after menopause, suggesting that the female hormone estrogen might be driving LAM tumor growth. Third, LAM tumors contain mutations in one of the two tuberous sclerosis (TSC) genes, which are the genes that are altered in the disease tuberous sclerosis. Finally, LAM tumors re-appear in transplanted lungs, suggesting an origin of the LAM cell that is outside of the lungs. Putting all of this information together, we proposed that LAM tumors may come from or behave like smooth muscle cells from the uterus, an estrogen sensitive organ found only in women. We shut off TSC2 expression only in the mouse uterus, and females developed LAM tumors in the uteri that metastasized to the lungs. Recent work looking specifically at genes expressed in individual LAM cells from human patients showed that in fact the LAM cells look just like uterine cells, confirming that LAM tumor cells might indeed originate from or share a similar origin as uterine cells. Interestingly, reflecting what is seen in LAM patients, the LAM tumors in the aforementioned mouse model required estrogen for significant growth. However, uterine cells isolated from these TSC2 knockout mice, as well as other existing LAM cell lines, had little estrogen sensitivity in the lab. These observations suggest that estrogen may not be directly stimulating LAM tumors cells – in fact, estrogen may be stimulating other cells that in turn promote LAM progression. In support of this concept, we find that estrogen stimulates the production and actions of immune cells called neutrophils, which in turn release a molecule called neutrophil elastase that then promotes LAM tumor cell proliferation. In the project described here, we will study how this estrogen to neutrophil to LAM cell pathway functions, which will reveal novel new therapeutic targets for LAM, including potentially blockade of estrogen signaling or neutrophil actions. We have already discovered some possible novel treatments that have been tested in animal models (e.g., blockers of neutrophil elastase or of neutrophil migration into tumors) and expect more to come out of these studies. We predict that within 3 years we will have some new treatment options that have been tested in our preclinical mouse models, and that within 5 years we will have novel therapies being tested in human patients with LAM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310281
Entities
People
- Stephen Hammes
Organizations
- United States Army
- University of Rochester