Antibody αPEP13h Reacts With Lymphangioleiomyomatosis Cells in Lung Nodules

Valencia, Julio C.; Steagall, Wendy K.; Zhang, Yi; Fetsch, Patricia; Abati, Andrea; Tsukada, Katsuya; Billings, Eric M.; Hearing, Vincent J.; Yu, Zu‐Xi; Pacheco–Rodriguez, Gustavo; Moss, Joel

doi:10.1378/chest.14-0380

Cited by 7 publications

(3 citation statements)

References 42 publications

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“…The expression of α-Smooth Muscle Actin and melanoma markers is used diagnostically to identify LAM cells in lung biopsies: however our use of a wider panel of markers suggests that α-Smooth Muscle Actin expression may be due both to the presence of LAM cells and fibroblasts. This, coupled with the presence of cells which do not express melanoma markers, including the recently described αPEP13h, a high sensitivity antibody targeting PMEL/gp100 [ 27 ], in LAM nodules suggest these lesions contain multiple cell types and suggest that cells similar to activated fibroblasts are present in LAM nodules, and are likely to contribute to the lung pathology of LAM.…”

Section: Discussionmentioning

confidence: 99%

Wild Type Mesenchymal Cells Contribute to the Lung Pathology of Lymphangioleiomyomatosis

et al. 2015

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Lymphangioleiomyomatosis (LAM) is a rare disease leading to lungs cysts and progressive respiratory failure. Cells of unknown origin accumulate in the lungs forming nodules and eventually resulting in lung cysts. These LAM cells are described as clonal with bi-allelic mutations in TSC-2 resulting in constitutive mTOR activation. However LAM nodules are heterogeneous structures containing cells of different phenotypes; we investigated whether recruited wild type cells were also present alongside mutation bearing cells. Cells were isolated from LAM lung tissue, cultured and characterised using microscopy, immunocytochemistry and western blotting. Fibroblast-like cells were identified in lung tissue using immunohistochemical markers. Fibroblast chemotaxis toward LAM cells was examined using migration assays and 3D cell culture. Fibroblast-like cells were obtained from LAM lungs: these cells had fibroblast-like morphology, actin stress fibres, full length tuberin protein and suppressible ribosomal protein S6 activity suggesting functional TSC-1/2 protein. Fibroblast Activation Protein, Fibroblast Specific Protein/S100A4 and Fibroblast Surface Protein all stained subsets of cells within LAM nodules from multiple donors. In a mouse model of LAM, tuberin positive host derived cells were also present within lung nodules of xenografted TSC-2 null cells. In vitro, LAM 621-101 cells and fibroblasts formed spontaneous aggregates over three days in 3D co-cultures. Fibroblast chemotaxis was enhanced two fold by LAM 621-101 conditioned medium (p=0.05), which was partially dependent upon LAM cell derived CXCL12. Further, LAM cell conditioned medium also halved fibroblast apoptosis under serum free conditions (p=0.03). Our findings suggest that LAM nodules contain a significant population of fibroblast-like cells. Analogous to cancer associated fibroblasts, these cells may provide a permissive environment for LAM cell growth and contribute to the lung pathology of LAM lung disease.

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Section: Discussionmentioning

confidence: 99%

Wild Type Mesenchymal Cells Contribute to the Lung Pathology of Lymphangioleiomyomatosis

et al. 2015

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“…In addition, the antipeptide antibody αPEP13h reacting with a C-peptide terminal of the Pmel17 protein identifies over 82% of the LAM cells in lung nodules, but HMB-45 identifies only 25%. 26 As LAM is such a rare condition, it is important to obtain a proper opinion from a specialist as early as possible and to discuss your individual case with an expert on the condition. Once LAM is diagnosed, effective treatment and management should be offered.…”

Section: Discussionmentioning

confidence: 99%

Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment

Liu¹,

Guo²,

Zhao³

et al. 2018

OTT

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Lymphangioleiomyomatosis (LAM) is a rare disease that generally affects young women and involves the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs (pulmonary LAM) and extrapulmonary sites (extrapulmonary LAM). This disease is rare in males. It is hard to distinguish between lung cancer and pulmonary LAM, especially during early stages. Herein, we present a case of a 66-year-old man with a small nodule in the right upper lobe that was first diagnosed as a lung malignancy using a chest CT scan. After a wedge dissection, a pathologist performed a histologic and immunohistochemical examination, and a diagnosis of pulmonary LAM was made. We further performed a 518-gene panel analysis using next-generation sequencing, and only three genes, BARD1, BLM, and BRCA2, were found to have mutations. We also provide a summary of the diagnosis and treatment of this disease.

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“…In addition, LAM cells exhibit positive immunoreactivity for estrogen and progesterone receptors [20,21], β-catenin [22,23], E-catherin [24], and epidermal growth factor receptor [25]. The antipeptide antibody αPEP13h, which reacts with a C-peptide terminal of the Pmel17 protein, and identifies over 82 % of the LAM cells in lung nodules whereas HMB-45 identified only 25 % [26]. …”

Section: Pathologymentioning

confidence: 99%

Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis

Taveira-DaSilva

Moss

2016

Expert Opinion on Orphan Drugs

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Introduction Lymphangioleiomyomatosis (LAM) is a disease of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas. Areas covered LAM is caused by proliferation of abnormal smooth muscle-like LAM cells containing mutations and perhaps epigenetic modifications of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins controlling the mechanistic target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex. LAM may present with dyspnea, recurrent pneumothorax or chylothorax. Pulmonary function tests show reduced flow rates and lung diffusion capacity. Exercise testing may reveal hypoxemia and ventilatory limitation. The severity and progression of disease may be assessed by computer tomography, and pulmonary function and exercise testing. mTOR inhibitors, (e.g., sirolimus) are effective in stabilizing lung function, and reducing the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas. Expert opinion Different clinical phenotypes including variable rates of disease progression and variable responses to therapy are seen in LAM patients. No one test is available that predicts the course of disease at the time of diagnosis. Further research regarding the molecular biology of LAM clinical phenotypes is warranted. Recent advances in the characterization of the pathogenesis of LAM are leading to the development of new therapies.

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Antibody αPEP13h Reacts With Lymphangioleiomyomatosis Cells in Lung Nodules

Cited by 7 publications

References 42 publications

Wild Type Mesenchymal Cells Contribute to the Lung Pathology of Lymphangioleiomyomatosis

Wild Type Mesenchymal Cells Contribute to the Lung Pathology of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment

Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis

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