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Erin Gibbons Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester Medical Center, Rochester, New York, USA
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA

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Briaunna M N Minor Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester Medical Center, Rochester, New York, USA
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA

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Stephen R Hammes Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester Medical Center, Rochester, New York, USA

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Abstract

Lymphangioleiomyomatosis (LAM) is a cystic lung disease found almost exclusively in genetic females and caused by small clusters of smooth muscle cell tumors containing mutations in one of the two tuberous sclerosis genes (TSC1 or TSC2). Significant advances over the past 2–3 decades have allowed researchers and clinicians to more clearly understand the pathophysiology of LAM, and therefore better diagnose and treat patients with this disease. Despite substantial progress, only one proven treatment for LAM is used in practice: mechanistic target of rapamycin complex 1 (mTORC1) inhibition with medications such as sirolimus. While mTORC1 inhibition effectively slows LAM progression in many patients, it is not curative, is not effective in all patients, and can be associated with significant side effects. Furthermore, the presence of established and accurate biomarkers to follow LAM progression is limited. That said, discovering additional diagnostic and treatment options for LAM is paramount. This review will describe recent advances in LAM research, centering on the origin and nature of the LAM cell, the role of estrogen in LAM progression, the significance of melanocytic marker expression in LAM cells, and the potential roles of the microenvironment in promoting LAM tumor growth. By appreciating these processes in more detail, researchers and caregivers may be afforded novel approaches to aid in the treatment of patients with LAM.

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Manisha Taya Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Maria de la Luz Garcia-Hernandez Division of Allergy/Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Javier Rangel-Moreno Division of Allergy/Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Briaunna Minor Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Erin Gibbons Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Stephen R Hammes Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Chronic inflammation promotes progression of many cancers, with circulating myeloid-derived suppressor cell (MDSC) levels correlating with poor prognosis. Here we examine effects of MDSCs on lymphangioleiomyomatosis (LAM), a rare disease occurring almost exclusively in women whereby estrogen-sensitive metastatic TSC2-null tumors grow throughout the lungs, markedly reducing pulmonary function. The LAM cell origin remains unknown; however, previous work demonstrated that Tsc2 inactivation in the mouse uterus induced estrogen-dependent myometrial tumors with nearly all features of LAM. Half of these animals developed metastatic myometrial tumors in the lungs, suggesting that LAM cells might originate from the myometrium, possibly explaining its overwhelming female prevalence and estrogen-sensitivity. Here we report that MDSC levels, and in particular granulocytic myeloid cell levels, are elevated in the periphery and in tumors of uterine-specific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impairs myometrial tumor growth. RNA and protein analysis of Tsc2-null myometrial tumors and xenografts demonstrate high expression and activity of the serine protease neutrophil elastase (NE), with selective qPCR studies indicating a stromal origin of the NE. Notably, treatment with sivelestat, a known NE inhibitor already approved for human use in some countries, reduces tumor growth similar to MDSC depletion. Furthermore, NE promotes Tsc2-null tumor cell growth, migration, and invasion in vitro. Finally, NE-expressing myeloid cells are present throughout the lungs of LAM patients but not controls. These data suggest that NE derived from granulocytic myeloid cells might directly promote LAM tumor cell progression and could be a novel therapeutic target for LAM.

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