Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses

Hayashi, Takuo; Kumasaka, Takashi; Mitani, Keiko; Okada, Yoshinori; Kondo, Takashi; Date, Hiroshi; Chen, Fengshi; Oto, Takahiro; Miyoshi, Shinichiro; Shiraishi, Takeshi; Iwasaki, Atsushi; Hara, Kieko; Saito, Tsuyoshi; Ando, Kenji; Kobayashi, Etsuko; Gunji-Niitsu, Yoko; Kunogi, Makiko; Takahashi, Kazuhisa; Yao, Takashi; Seyama, Kuniaki

doi:10.1016/j.humpath.2015.11.002

Cited by 23 publications

(27 citation statements)

References 18 publications

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“…Findings suggested high mTORC1 and mTORC2 activity in LAM cells in 91% and 55% of the cases, respectively. High mTORC1 activity in LAM cells is consistent with previous observations [19,25]. Our findings suggest that high mTORC2 activity may also play a role in the pathobiology of LAM.…”

Section: Discussionsupporting

confidence: 92%

In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis

et al. 2018

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Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease with features of a low-grade neoplasm. It is primarily caused by mutations in TSC1 or TSC2 genes. Sirolimus, an inhibitor of mTOR complex 1 (mTORC1), slows down disease progression in some, but not all patients. Hitherto, other potential therapeutic targets such as mTOR complex 2 (mTORC2) and various metabolic pathways have not been investigated in human LAM tissues. The aim of this study was to assess activities of mTORC1, mTORC2 and various metabolic pathways in human LAM tissues through analysis of protein expression. Immunohistochemical analysis of p-S6 (mTORC1 downstream protein), Rictor (mTORC2 scaffold protein) as well as GLUT1, GAPDH, ATPB, GLS, MCT1, ACSS2 and CPT1A (metabolic pathway markers) were performed on lung tissue from 11 patients with sporadic LAM. Immunoreactivity was assessed in LAM cells with bronchial smooth muscle cells as controls. Expression of p-S6, Rictor, GAPDH, GLS, MCT1, ACSS2 and CPT1A was significantly higher in LAM cells than in bronchial smooth muscle cells (P<.01). No significant differences were found between LAM cells and normal bronchial smooth muscle cells in GLUT1 and ATPB expression. The results are uniquely derived from human tissue and indicate that, in addition to mTORC1, mTORC2 may also play an important role in the pathobiology of LAM. Furthermore, glutaminolysis, acetate utilization and fatty acid β-oxidation appear to be the preferred bioenergetic pathways in LAM cells. mTORC2 and these preferred bioenergetic pathways appear worthy of further study as they may represent possible therapeutic targets in the treatment of LAM.

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Section: Discussionsupporting

confidence: 92%

In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis

et al. 2018

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“…Other researchers have shown the expression of pS6 and p4E-BP1 in LAM lung tissue [21]. We showed here, for the first time, that LAM lung lesions express peIF4E (Ser209) ( Figure 2C).…”

Section: Lam Lung Cells Express Peif4e and The Selective Mnk1/2 Inhibsupporting

confidence: 70%

Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor

et al. 2019

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Lymphangioleiomyomatosis (LAM) is a rare metastatic cystic lung disease due to a mutation in a TSC tumor suppressor, resulting in hyperactive mTOR growth pathways. Sirolimus (rapamycin), an allosteric mTORC1 inhibitor, is a therapeutic option for women with LAM but it only maintains lung volume during treatment and does not provide benefit for all LAM patients. The two major mTORC1 protein synthesis pathways are via S6K/S6 or 4E-BP/eIF4E activation. We aimed to investigate rapamycin in combination with compounds that target associated growth pathways, with the potential to be additive to rapamycin. In this study we demonstrated that rapamycin, at a clinically tolerable concentration (10 nM), inhibited the phosphorylation of S6, but not the critical eIF4E releasing Thr 37/46 phosphorylation sites of 4E-BP1 in TSC2-deficient LAM-derived cells. We also characterized the abundant protein expression of peIF4E within LAM lesions. A selective MNK1/2 inhibitor eFT508 inhibited the phosphorylation of eIF4E but did not reduce TSC2-null cell growth. In contrast, a PI3K/mTOR inhibitor omipalisib blocked the phosphorylation of Akt and both S6K/S6 and 4E-BP/eIF4E branches, and additively decreased the growth of TSC2-null cells with rapamycin. Omipalisib, or another inhibitor of both major mTORC1 growth pathways and pAkt, might provide therapeutic options for TSC2-deficient cancers including, but not limited to, LAM.

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“…While this pattern is even greater in the study of beta-agonist subtype in patients receiving sirolimus (87.5% of use of short-and long-acting betaagonists is in conjunction with steroids versus 42.9% for long-acting beta-agonists plus steroids), the total number of long-acting betaagonist visits (35 visits) is far fewer than that of both short-and long-acting beta-agonists (104 visits) and may not accurately reflect the effect on pulmonary function of long-acting beta-agonists alone. Late-stage LAM lungs have been shown to have chronic inflammation (11), and so a combination of beta-agonists to reduce airway obstruction plus a corticosteroid may be appropriate in some cases of LAM. Chronic inflammation in chronic obstructive pulmonary disease may be resistant to corticosteroids (67); peripheral blood mononuclear cells from these patients showed increased mTOR activity (68).…”

Section: Discussionmentioning

confidence: 99%

“…While LAM cells may be largely parenchymal, Hayashi et al (11) showed bronchial involvement by LAM cells in explanted lungs of all 30 patients examined. A significant portion of these patients also had markers of chronic inflammation (e.g., mononuclear cell infiltration, goblet cell hyperplasia, squamous cell metaplasia, thickening of basal lamina) (11). Although LAM lesions were originally considered to represent a benign neoplasm, LAM is now accepted as a cancer with metastatic dissemination of cancer-like LAM cells (12).…”

mentioning

confidence: 92%

“…LAM cells are believed to proliferate in axial lymphatics and lung interstitium, leading to airway and lymphatic obstruction (2,10). While LAM cells may be largely parenchymal, Hayashi et al (11) showed bronchial involvement by LAM cells in explanted lungs of all 30 patients examined. A significant portion of these patients also had markers of chronic inflammation (e.g., mononuclear cell infiltration, goblet cell hyperplasia, squamous cell metaplasia, thickening of basal lamina) (11).…”

mentioning

confidence: 99%

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Effect of beta-agonists on LAM progression and treatment

Kang

Steagall

Stylianou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes and/or The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.

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Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses

Cited by 23 publications

References 18 publications

In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis

In situ analysis of mTORC1/2 and cellular metabolism–related proteins in human Lymphangioleiomyomatosis

Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor

Effect of beta-agonists on LAM progression and treatment

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