Steroid Receptors in Pulmonary Lymphangiomyomatosis

Brentani, Maria M.C.; Carvalho, Carlos Roberto Ribeiro; Saldiva, Paulo Hilário Nascimento; Pacheco, Mariana Poltronieri; Oshima, Celina Tizuko Fujiyama

doi:10.1378/chest.85.1.96

Cited by 84 publications

(40 citation statements)

References 22 publications

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“…The exclusive occurrence of S-LAM in females in association with the observations that S-LAM may be exacerbated by pregnancy (11) and by exogenous estrogens led to a variety of hormone-based therapies (12)(13)(14)(15). These developments were paralleled by the finding that LAM cells express sex steroid receptors (16)(17)(18). Subsequent immunohistochemical studies of lung tissue specimens from patients with LAM demonstrated that the cells express ␣-smooth muscle actin (19), confirming Cornog and Enterline's (8) original description of the LAM cell as a smooth muscle cell.…”

Section: Characterization Of the Lam Cellmentioning

confidence: 99%

Molecular Pathogenesis of Lymphangioleiomyomatosis

Juvet

McCormack²,

Kwiatkowski³

et al. 2007

Am J Respir Cell Mol Biol

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Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.Keywords: tuberous sclerosis; TSC1; TSC2; mTOR; signal transduction; estrogen Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease of uncertain etiology that affects young women. LAM cysts are formed as a result of the proliferation of an abnormal smooth muscle-like cell, the LAM cell. The mechanism by which LAM cells cause this architectural distortion of the lung is unknown. The clinical course of LAM is frequently inexorable, leading to death or lung transplantation in 10 to 15 years, although recent studies indicate that there is much variability in the natural history of the disorder (1, 2). The most common clinical manifestation is the insidious onset of exertional dyspnea; patients may also experience a nonproductive cough. Other common features include spontaneous pneumothorax, which results from cyst rupture, and chylothorax, which results from obstruction of pulmonary lymphatics and hilar lymph nodes by the slowly proliferating LAM cells. Less frequently, hemoptysis or chyloptysis may occur (1, 2).Most of the current therapies for LAM are supportive in nature. Bronchodilators are offered because many patients have obstructive physiology, often with some degree of reversibility, on pulmonary function testing. Oxygen is provided to patients with significant hypoxia. Current recommendations stipulate

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Section: Characterization Of the Lam Cellmentioning

confidence: 99%

Molecular Pathogenesis of Lymphangioleiomyomatosis

Juvet

McCormack²,

Kwiatkowski³

et al. 2007

Am J Respir Cell Mol Biol

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“…Brentani et al reported the presence of estrogen, progesterone and glucocorticoids receptors in the lung tissue of patients with LAM. (6) Another study confirmed estrogen and progesterone receptor positivity in angiomyolipoma. (7) Yu et al confirmed that estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth in culture.…”

mentioning

confidence: 86%

Evolução da função pulmonar após tratamento com goserelina em pacientes com linfangioleiomiomatose

et al. 2011

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In the atypical smooth muscle cells that are characteristic of lymphangioleiomyomatosis (LAM), there are estrogen and progesterone receptors. Therefore, anti-hormonal therapy, despite having produced controversial results, can be considered a treatment option. The objective of this retrospective study was to evaluate hormonal and spirometric data for nine women with LAM after one year of treatment with goserelin. The mean increase in FEV 1 and FVC was 80 mL and 130 mL, respectively. There was effective blockage of the hormonal axis. It is still not possible to exclude a potential beneficial effect of the use of gonadotropin-releasing hormone analogues in LAM patients, which underscores the need for randomized trials.Keywords: Lymphangioleiomyomatosis; Spirometry; Goserelin. ResumoNas células musculares lisas atípicas características da linfangioleiomiomatose (LAM) encontram-se receptores de estrogênio e progesterona, de modo que o tratamento anti-hormonal pode ser considerado uma opção, mas ainda com resultados controversos. O objetivo deste trabalho foi avaliar retrospectivamente parâmetros hormonais e espirométricos em nove mulheres com LAM após o tratamento com goserelina por um ano. Houve um aumento médio de 80 mL e 130 mL, respectivamente, em VEF 1 e CVF, assim como bloqueio hormonal efetivo. Ainda não se pode excluir um potencial efeito favorável da utilização de análogos de hormônio liberador de gonadotrofina em pacientes com LAM, reforçando a necessidade de ensaios randomizados.

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“…Many studies have shown estrogen receptor alpha (ERa) and progesterone receptor (PR) expression by LAM cells, [28][29][30][31][32] and our group has found that angiomyolipomas from sporadic LAM patients also express ERa and PR. 31 Howe et al found that estrogen promotes the proliferation of Tsc2-null ELT3 cells in vitro and the growth of xenograft subcutaneous tumors in vivo.…”

Section: Estrogen Promotes the Survival And Metastasis Of Tsc2-null Cmentioning

confidence: 96%

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

Henske

2010

Lymphatic Research and Biology

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Research interest in lymphangioleiomyomatosis (LAM) has grown dramatically in the past decade, particularly among cancer biologists. There are at least two reasons for this: first, the discovery in the year 2000 that LAM cells carry TSC2 gene mutations, linking LAM with cellular pathways including the PI3K=Akt=mTOR axis, and allowing the Tuberous Sclerosis Complex (TSC)-regulated pathways that are believed to underlie LAM pathogenesis to be studied in cells, yeast, Drosophila, and mice. A second reason for the rising interest in LAM is the discovery that LAM cells can travel to the lung, including repopulating a donor lung after lung transplantation, despite the fact that LAM cells are histologically benign. This ''benign metastasis'' underpinning suggests that elucidating LAM pathogenesis will unlock a set of fundamental mechanisms that underlie metastatic potential in the context of a cell that has not yet undergone malignant transformation. Here, we will outline the data supporting the metastatic model of LAM, consider the biochemical and cellular mechanisms that may enable LAM cells to metastasize, including both cell autonomous and non-cell autonomous factors, and highlight a mouse model in which estrogen promotes the metastasis and survival of TSC2-deficient cells in a MEKdependent manner. We propose a multistep model of LAM cell metastasis that highlights multiple opportunities for therapeutic intervention. Taken together, the metastatic behavior of LAM cells and the involvement of tumorrelated signaling pathways lead to optimism that cancer-related paradigms for diagnosis, staging, and therapy will lead to therapeutic breakthroughs for women living with LAM.

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Steroid Receptors in Pulmonary Lymphangiomyomatosis

Cited by 84 publications

References 22 publications

Molecular Pathogenesis of Lymphangioleiomyomatosis

Molecular Pathogenesis of Lymphangioleiomyomatosis

Evolução da função pulmonar após tratamento com goserelina em pacientes com linfangioleiomiomatose

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

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