Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of r...
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| Format: | Online |
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Public Library of Science
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500593/ |
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pubmed-45005932015-07-17 Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness Ruiz de Garibay, Gorka Herranz, Carmen Llorente, Alicia Boni, Jacopo Serra-Musach, Jordi Mateo, Francesca Aguilar, Helena Gómez-Baldó, Laia Petit, Anna Vidal, August Climent, Fina Hernández-Losa, Javier Cordero, Álex González-Suárez, Eva Sánchez-Mut, José Vicente Esteller, Manel Llatjós, Roger Varela, Mar López, José Ignacio García, Nadia Extremera, Ana I. Gumà, Anna Ortega, Raúl Plà, María Jesús Fernández, Adela Pernas, Sònia Falo, Catalina Morilla, Idoia Campos, Miriam Gil, Miguel Román, Antonio Molina-Molina, María Ussetti, Piedad Laporta, Rosalía Valenzuela, Claudia Ancochea, Julio Xaubet, Antoni Casanova, Álvaro Pujana, Miguel Angel Research Article Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. Public Library of Science 2015-07-13 /pmc/articles/PMC4500593/ /pubmed/26167915 http://dx.doi.org/10.1371/journal.pone.0132546 Text en © 2015 Ruiz de Garibay et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Ruiz de Garibay, Gorka Herranz, Carmen Llorente, Alicia Boni, Jacopo Serra-Musach, Jordi Mateo, Francesca Aguilar, Helena Gómez-Baldó, Laia Petit, Anna Vidal, August Climent, Fina Hernández-Losa, Javier Cordero, Álex González-Suárez, Eva Sánchez-Mut, José Vicente Esteller, Manel Llatjós, Roger Varela, Mar López, José Ignacio García, Nadia Extremera, Ana I. Gumà, Anna Ortega, Raúl Plà, María Jesús Fernández, Adela Pernas, Sònia Falo, Catalina Morilla, Idoia Campos, Miriam Gil, Miguel Román, Antonio Molina-Molina, María Ussetti, Piedad Laporta, Rosalía Valenzuela, Claudia Ancochea, Julio Xaubet, Antoni Casanova, Álvaro Pujana, Miguel Angel |
| spellingShingle |
Ruiz de Garibay, Gorka Herranz, Carmen Llorente, Alicia Boni, Jacopo Serra-Musach, Jordi Mateo, Francesca Aguilar, Helena Gómez-Baldó, Laia Petit, Anna Vidal, August Climent, Fina Hernández-Losa, Javier Cordero, Álex González-Suárez, Eva Sánchez-Mut, José Vicente Esteller, Manel Llatjós, Roger Varela, Mar López, José Ignacio García, Nadia Extremera, Ana I. Gumà, Anna Ortega, Raúl Plà, María Jesús Fernández, Adela Pernas, Sònia Falo, Catalina Morilla, Idoia Campos, Miriam Gil, Miguel Román, Antonio Molina-Molina, María Ussetti, Piedad Laporta, Rosalía Valenzuela, Claudia Ancochea, Julio Xaubet, Antoni Casanova, Álvaro Pujana, Miguel Angel Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| author_facet |
Ruiz de Garibay, Gorka Herranz, Carmen Llorente, Alicia Boni, Jacopo Serra-Musach, Jordi Mateo, Francesca Aguilar, Helena Gómez-Baldó, Laia Petit, Anna Vidal, August Climent, Fina Hernández-Losa, Javier Cordero, Álex González-Suárez, Eva Sánchez-Mut, José Vicente Esteller, Manel Llatjós, Roger Varela, Mar López, José Ignacio García, Nadia Extremera, Ana I. Gumà, Anna Ortega, Raúl Plà, María Jesús Fernández, Adela Pernas, Sònia Falo, Catalina Morilla, Idoia Campos, Miriam Gil, Miguel Román, Antonio Molina-Molina, María Ussetti, Piedad Laporta, Rosalía Valenzuela, Claudia Ancochea, Julio Xaubet, Antoni Casanova, Álvaro Pujana, Miguel Angel |
| author_sort |
Ruiz de Garibay, Gorka |
| title |
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| title_short |
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| title_full |
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| title_fullStr |
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| title_full_unstemmed |
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness |
| title_sort |
lymphangioleiomyomatosis biomarkers linked to lung metastatic potential and cell stemness |
| description |
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. |
| publisher |
Public Library of Science |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500593/ |
| _version_ |
1613247276007817216 |