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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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Graphical abstract

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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Hen Prizant Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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

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Irina Lerman Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Allison Light Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Aritro Sen Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Soumya Mitra Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA

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Thomas H Foster Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA

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

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Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse Tsc2-null myometrial tumors exhibit nearly all the features of LAM, including mTORC1/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in Tsc2-null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1/S6K signaling. Additionally, we find that MMP-2 and -9, as well as neutrophil elastase (NE), are overexpressed in Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers.

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

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Manisha Taya Division of Hematology and Oncology, UT Southwestern, Dallas, Texas, USA

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Huixing Wu Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Samia H Lopa Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA

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Joel Moss Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA

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Elizabeth P Henske Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Francis X McCormack Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Stephen R Hammes Department of Microbiology and Immunology University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here, we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

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Hans K Ghayee
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Bas Havekes Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Eleonora P M Corssmit Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Graeme Eisenhofer Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Stephen R Hammes
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Zahid Ahmad
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Alexander Tessnow
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Ivica Lazúrová Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Karen T Adams Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Antonio T Fojo Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Karel Pacak Division of Endocrinology, Reproductive Biology and Medicine Program, Department of Endocrinology and Metabolism, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, Department of Medicine, Medical Oncology Branch, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA

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Richard J Auchus
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Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.

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