Lymphangioleiomyomatosis: What do we know and what are we looking for?

Unità Operativa di Pneumologia e Terapia Semi-Intensiva Respiratoria--Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare Ospedale San Giuseppe, via San Vittore 12, Milan, Italy.
European Respiratory Review 03/2011; 20(119):34-44. DOI: 10.1183/09059180.00011010
Source: PubMed


Lymphangioleiomyomatosis (LAM) is a rare disease characterised by proliferation of abnormal smooth muscle-like cells (LAM cells) leading to progressive cystic destruction of the lung, lymphatic abnormalities and abdominal tumours. It affects predominantly females and can occur sporadically or in patients with tuberous sclerosis complex. This review describes the recent progress in our understanding of the molecular pathogenesis of the disease and LAM cell biology. It also summarises current therapeutic approaches and the most promising areas of research for future therapeutic strategies.

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    • "Krymskaya and colleagues have previously demonstrated a role for regulators of smooth muscle function in the pathogenesis of LAM, identifying that RhoA is activated in TSC2-deficient cells [41], [42]. Smooth muscle-like LAM cells can be identified in vivo in two different morphologic states, a highly proliferative “spindle shape” and a more static “epithelioid” state [43]; the pathways that regulate the phenotypic switch of LAM cells is unknown. Third, it is possible that miR-21 induces a pro-inflammatory state that promotes the survival and metastasis of TSC2-deficient LAM cells. "
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    ABSTRACT: Lymphangioleiomyomatosis (LAM), a multisystem disease of women, is manifest by the proliferation of smooth muscle-like cells in the lung resulting in cystic lung destruction. Women with LAM can also develop renal angiomyolipomas. LAM is caused by mutations in the tuberous sclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target of Rapamycin (mTOR) signaling. The mTOR inhibitor, Rapamycin, stabilizes lung function in LAM and decreases the volume of renal angiomyolipomas, but lung function declines and angiomyolipomas regrow when treatment is discontinued, suggesting that factors induced by mTORC1 inhibition may promote the survival of TSC2-deficient cells. Whether microRNA (miRNA, miR) signaling is involved in the response of LAM to mTORC1 inhibition is unknown. We identified Rapamycin-dependent miRNA in LAM patient angiomyolipoma-derived cells using two separate screens. First, we assayed 132 miRNA of known significance to tumor biology. Using a cut-off of >1.5-fold change, 48 microRNA were Rapamycin-induced, while 4 miRs were downregulated. In a second screen encompassing 946 miRNA, 18 miRs were upregulated by Rapamycin, while eight were downregulated. Dysregulation of miRs 29b, 21, 24, 221, 106a and 199a were common to both platforms and were classified as candidate "RapamiRs." Validation by qRT-PCR confirmed that these microRNA were increased. miR-21, a pro-survival miR, was the most significantly increased by mTOR-inhibition (p<0.01). The regulation of miR-21 by Rapamycin is cell type independent. mTOR inhibition promotes the processing of the miR-21 transcript (pri-miR-21) to a premature form (pre-miR-21). In conclusion, our findings demonstrate that Rapamycin upregulates multiple miRs, including pro-survival miRs, in TSC2-deficient patient-derived cells. The induction of miRs may contribute to the response of LAM and TSC patients to Rapamycin therapy.
    PLoS ONE 03/2013; 8(3):e60014. DOI:10.1371/journal.pone.0060014 · 3.23 Impact Factor
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    European Respiratory Review 01/2011;
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    ABSTRACT: Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
    Nature medicine 11/2011; 17(11):1371-80. DOI:10.1038/nm.2545 · 27.36 Impact Factor
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