Development of a Lymphangioleiomyomatosis Model by Endonasal Administration of Human TSC2−/− Smooth Muscle Cells in Mice

Lesma, Elena; Chiaramonte, Eloisa; Isaia, Eleonora; Grande, V.; Ancona, Silvia; Orpianesi, E.; Giulio, Anna Maria Di; Gorio, Alfredo

doi:10.1016/j.ajpath.2012.05.017

Cited by 10 publications

(18 citation statements)

References 39 publications

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“…15, 30, or 60 weeks after endonasal cell administration, mice were sacrificed by exsanguination under 4% chloral hydrate anesthesia. Lungs and lymph nodes were removed as described by Lesma et al [ 20 ]. All specimens were fixed in 4% paraformaldehyde at 4°C overnight and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

Anti-EGFR Antibody Reduces Lung Nodules by Inhibition of EGFR-Pathway in a Model of Lymphangioleiomyomatosis

Lesma

Chiaramonte

Ancona

et al. 2015

BioMed Research International

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EGFR belongs to the HER/ErbB family of tyrosine kinase receptors and its activation in cancer cells has been linked with increased proliferation, angiogenesis, and metastasis. Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that occurs sporadically or in association with tuberous sclerosis complex (TSC), a genetic, multisystem disorder characterized by hamartomas in several organs. From chylous of a LAM/TSC patient, we previously isolated smooth muscle-like LAM/TSC cells whose proliferation depends on EGF and monoclonal anti-EGFR antibodies reduced proliferation and caused cell death. We demonstrated that the dependency from EGF was caused by the absence of tuberin. To study the role of EGFR pathway in vivo, we developed a mouse model by administration of LAM/TSC cells to female nude mice. LAM/TSC cells caused pulmonary airspace enlargement and, after 30 weeks, nodule formation which express EGFR. Anti-EGFR antibody decreased the number and dimension of lung nodules likely for the inhibition of Erk and S6 signaling, reversed the pulmonary alterations, and reduced lymphatic and blood vessels. Moreover, in pulmonary nodules anti-EGFR antibody reduced the positivity to estrogen and progesterone receptors which enhance survival of LAM cells and Snail expression. These results suggest that the inhibition of EGFR signalling has a potential in treatment of LAM/TSC lung alterations.

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Section: Methodsmentioning

confidence: 99%

Anti-EGFR Antibody Reduces Lung Nodules by Inhibition of EGFR-Pathway in a Model of Lymphangioleiomyomatosis

Lesma

Chiaramonte

Ancona

et al. 2015

BioMed Research International

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“…In control and LAM/TSC cell-administeredmice LYVE 1 lymphatic vessel profile was within the myometrial circular and longitudinal muscle layers while after the administration of rapamycin and anti-EGFR antibody, immunoreactivity was mainly localized in the perimetrium. Thus both treatments affected lymphatic vessel distribution in uteri while they were effective in the control of lymphangiogenesis in lungs in our previous mouse model developed with the administration of TSC2 -/-ASM cells [23].…”

Section: Discussionmentioning

confidence: 81%

“…Anti-EGFR antibody is efficacious in treating several types of cancer such as colorectal and head-and-neck cancers [36]. We previously showed that anti-EGFR antibody more efficiently than rapamycin reversed the pulmonary alterations caused by TSC2 -/-ASM cell administration [23]. In this case the two agents had similar effects in reducing the number and, likely, the infiltration of LAM/TSC cells in uterus.…”

Section: Discussionmentioning

confidence: 84%

“…Recently, the generation of a variety of mouse models by the injection of TSC2-deficient cells in specific conditions has given new input to study the invasive features of TSC2-deficient cells providing useful systems for in vivo drug testing [23,27,28]. We previously reported the development of an animal model of LAM through the endonasal administration of human TSC2 -/-ASM cells that infiltrate lymph nodes and lungs with consequent enlargement of the alveolar spaces [23]. Rapamycin and, more specifically, anti-EGFR antibody counteract these pulmonary lesions caused by the administration of TSC2 -/-ASM cells.…”

Section: Discussionmentioning

confidence: 99%

“…Lymphatic involvement in human LAM has been demonstrated by the observation of higher number of lymphatics in the lungs and LAM lesions, and in mice lungs after inoculation of TSC2 -/-ASM cells [22,23]. However, after LAM/TSC administration immunoreactivity to LYVE 1, a well known lymphatic capillary marker and lymph-specific receptor for hyaluronan, was unchanged in uterus ( Figure 4A) [24].…”

Section: Effect Of Anti-egfr Ab and Rapamycin On Angiogenesis And Lymmentioning

confidence: 99%

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LAM/TSC Cell Migration to Uterus in an Experimental Model of Lymphangioleiomyomatosis. Regulation by Anti-Epidermal Growth Factor Receptor Antibody and Rapamycin

Lesma

Chiaramonte²,

Ancona³

et al. 2014

J Cytol Histol

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Lymphangioleiomyomatosis (LAM) is a rare lung disease affecting almost exclusively women, characterized by the invasion and abnormal proliferation of smooth muscle-like cells in pulmonary parenchyma and axial lymphatics. LAM cells bear mutations in Tuberous Sclerosis Complex (TSC) genes. It has been hypothesized that uterus might be the primary site of origin and one of the most frequent metastatic or disseminated site of LAM cells. We developed a mouse model to study the migratory and invasive properties of human LAM/TSC cells to the uterus. We also examined the action of rapamycin and anti-Epidermal Growth Factor Receptor (EGFR) antibody. LAM/TSC cells were endonasally administered to 3 week old immunodeficient female nude mice. 5 months later mice were divided in 4 groups: control, LAM/TSC cell-administered mice, LAM/TSC cell-administered mice treated with rapamycin, and LAM/TSC cell-administered mice treated with anti-EGFR antibody. Drugs were administered for one months. Uteri were analysed for the presence of human LAM/TSC cells by COX IV antibody, lymphangiogenesis by LYVE 1 expression and angiogenesis by counting blood vessels. LAM/TSC cells migrated to the uterus without causing any morphological lesion. Interestingly, LAM/TSC cells increased the number of blood vessels while did not cause any alteration in lymphatics vessels. Anti-EGFR antibody and rapamycin reduced the number of human LAM/TSC and counteracted the proliferation of blood vessels in uteri. Although both drugs did not change the expression of LYVE 1, localization of lymphatics was mainly in the perimetrium after drug treatment. Our data describe the strong invasive capability of human LAM/TSC cells which migrated to the uterus. LAM/ TSC cells presence is accompanied by increased angiogenesis. Anti-EGFR antibody and rapamycin were effective in reducing the LAM/TSC cell number and blood vessel proliferation.

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New Indications of mTOR Inhibitors in Rare Tumors

Shah

Stergiopoulos²,

Lebwohl

2016

mTOR Inhibition for Cancer Therapy: Past, Present and Future

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Development of a Lymphangioleiomyomatosis Model by Endonasal Administration of Human TSC2−/− Smooth Muscle Cells in Mice

Cited by 10 publications

References 39 publications

Anti-EGFR Antibody Reduces Lung Nodules by Inhibition of EGFR-Pathway in a Model of Lymphangioleiomyomatosis

Anti-EGFR Antibody Reduces Lung Nodules by Inhibition of EGFR-Pathway in a Model of Lymphangioleiomyomatosis

LAM/TSC Cell Migration to Uterus in an Experimental Model of Lymphangioleiomyomatosis. Regulation by Anti-Epidermal Growth Factor Receptor Antibody and Rapamycin

New Indications of mTOR Inhibitors in Rare Tumors

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