Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

PLoS One. 2015 Jul 13;10(7):e0132546. doi: 10.1371/journal.pone.0132546. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood*
  • Breast Neoplasms / blood*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Gene Expression Profiling
  • Humans
  • Lung Neoplasms / blood*
  • Lung Neoplasms / secondary
  • Lymphangioleiomyomatosis / blood*
  • Lymphangioleiomyomatosis / pathology
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / pathology*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics

Substances

  • Biomarkers, Tumor
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins

Associated data

  • GEO/GSE68324

Grants and funding

This work was funded by the Government of Catalonia grant SGR 2014-364, the “Red Temática de Investigación Colaborativa en Cáncer” grant RD12/0036/0008, the Telemaraton 2014 “Todos Somos Raros, Todos Somos Únicos” grant P35, the Spanish Ministry of Health “Instituto de Salud Carlos III Fondo de Investigación Sanitaria” grant PI12/01528, and a Spanish Society of Pneumology and Thoracic Surgery (Sociedad Española de Neumología y Cirugía Torácica, SEPAR) grant for 2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.