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Lymphangioleiomyomatosis Biomarkers Linked To Lung Metastatic Potential And Cell Stemness
Gorka Ruiz de Garibay, C. Herranz, A. Llorente, J. Boni, J. Serra-Musach, F. Mateo, H. Aguilar, Laia Gómez-Baldó, A. Petit, A. Vidal, F. Climent, J. Hernández-Losa, Á. Cordero, E. González-Suárez, J. Sánchez-Mut, M. Esteller, R. Llatjós, M. Varela, J. I. López, Nadia Garcia, Ana I. Extremera, A. Gumà, R. Ortega, M. Pla, A. Fernández, S. Pernas, C. Falo, I. Morilla, Miriam Campos, Miguel Gil, A. Roman, M. Molina-Molina, P. Ussetti, R. Laporta, C. Valenzuela, J. Ancochea, A. Xaubet, Á. Casanova, M. A. Pujana
Published 2015 · Biology, Medicine
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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.
This paper references
Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma in situ
W. Boecker (2002)
Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis
Sean D. McAllister (2010)
The translational landscape of mTOR signalling steers cancer initiation and metastasis
A. C. Hsieh (2012)
Adams JC The roles of fascins in health and disease
Y Hashimoto (2011)
The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis.
A. Taveira-DaSilva (2010)
The mammary stem cell hierarchy.
N. Fu (2014)
Avinash Gautam (2016)
Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis.
Xiong Cai (2010)
Tumor Metastasis: Molecular Insights and Evolving Paradigms
Scott Valastyan (2011)
ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
C. Ginestier (2007)
mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization
B. Gan (2008)
Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis.
I. Bittmann (2003)
Downregulation of estrogen and progesterone receptors in the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy. An immunohistochemical study.
K. Matsui (2000)
Pelletier J eIF 4 F suppression in breast cancer affects maintenance and progression
Z Nasr (2013)
The roles of fascins in health and disease
Y. Hashimoto (2011)
Subtypes of breast cancer show preferential site of relapse.
M. Smid (2008)
The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis
Sean P. Delaney (2014)
Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism.
M. Karbowniczek (2003)
Comprehensive molecular portraits of human breast tumours
Aleix Prat Aparicio (2012)
eIF4F suppression in breast cancer affects maintenance and progression
Z. Nasr (2013)
Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis.
Denise M Crooks (2004)
Molecular portraits of human breast tumours
C. Perou (2000)
Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.
Elizabeth E Romero-Lanman (2012)
Lymphat Res Biol
F Blei (2011)
BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3
Qi-Long Ying (2003)
Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
D. Hancock (2012)
M. Rahalkar (2009)
Genes that mediate breast cancer metastasis to lung
A. Minn (2005)
CD49f and CD61 identify Her2/neu-induced mammary tumor initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling
Pang-Kuo Lo (2012)
self - renewal in collaboration with STAT 3
EE Romero-Lanman (2003)
Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival
N. P. Tobin (2015)
TCGA Comprehensive molecular portraits of human breast tumours doi: 10.1038/nature11412 PMID: 23000897 Lymphangioleiomyomatosis and Breast Cancer Metastasis Link PLOS ONE | DOI:10.1371/journal.pone
Id family of helix-loop-helix proteins in cancer
J. Perk (2005)
Reduced Argininosuccinate Synthetase Is a Predictive Biomarker for the Development of Pulmonary Metastasis in Patients with Osteosarcoma
E. Kobayashi (2010)
Lymphangioleiomyomatosis: a clinical update.
F. McCormack (2008)
Lymphangioleiomyomatosis: a clinical update. Chest
FX McCormack (2008)
Benezra R Id1 maintains embryonic stem cell selfrenewal by up-regulation of Nanog and repression of Brachyury expression
E E Romero-Lanman (2012)
Tuberous sclerosis complex.
M. Islam (2015)
Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
C. Burger (2011)
Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis.
K. Badri (2013)
TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex
D. Muzykewicz (2009)
Lymphangiomatosis: clinical overview.
F. Blei (2011)
Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis
T. Sato (2002)
In pulmonary lymphangioleiomyomatosis expression of progesterone receptor is frequently higher than that of estrogen receptor
L. Gao (2014)
Small-Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells
Helena Mistry (2013)
KEGG for integration and interpretation of large-scale molecular data sets
M. Kanehisa (2012)
Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm.
F. McCormack (2012)
Slug and Sox 9 Cooperatively Determine the Mammary Stem Cell State Citation
Henske EP The tuberous sclerosis complex
P B Crino (2006)
Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State
Wenjun Guo (2012)
Thiele EA TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex
D A Muzykewicz (2009)
Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer
H-J Lin (2005)
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Aravind Subramanian (2005)
Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis.
S. C. Chu (1999)
Reconstructing lineage hierarchies of the distal lung epithelium using single cell RNA-seq
Barbara Treutlein (2014)
Comprehensive molecular portraits of human breast tumors
D. Koboldt (2012)
mTOR activation, lymphangiogenesis, and estrogen-mediated cell survival: the "perfect storm" of pro-metastatic factors in LAM pathogenesis.
J. Yu (2010)
The role of chemokines in migration of metastatic-like lymphangioleiomyomatosis cells.
G. Pacheco-Rodríguez (2010)
TSC1 and TSC2mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex
DA Muzykewicz (2009)
An emerging role for TOR signaling in mammalian tissue and stem cell physiology
Ryan C. Russell (2011)
Tanabe M KEGG for integration and interpretation of largescale molecular data sets
M Kanehisa (2012)
Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through ROCK2 signalling
I. Ferrer (2014)
Mutational analysis of the tuberous sclerosis geneTSC2 in patients with pulmonary lymphangioleiomyomatosis
A. Astrinidis (2000)
with properties of stem cells
S Valastyan (2008)
Visvader JE The mammary stem cell hierarchy
N Fu (2014)
A Review of the
Robert Wolpert (1985)
Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.
L. Soroceanu (2013)
Lymphangioleiomyomatosis: a disease involving the lymphatic system.
K. Seyama (2010)
Id Proteins - Tumor Markers or Oncogenes?
J. Hasskarl (2002)
Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.
T. Carsillo (2000)
Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes.
W. Jiang (2005)
J. Kretz (1942)
Breast carcinoma with positive results for melanoma marker (HMB-45). HMB-45 immunoreactivity in normal and neoplastic breast.
F. Bonetti (1989)
Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer
Y. Wang (2005)
Genetic heterogeneity of circulating cells from patients with lymphangioleiomyomatosis with and without lung transplantation.
W. K. Steagall (2015)
Lymphangioleiomyomatosis: A review.
Donald W. Hohman (2008)
proteins—tumor markers or oncogenes
J Hasskarl (2002)
TACC3-TSC2 maintains nuclear envelope structure and controls cell division
Laia Gómez-Baldó (2010)
Analysis of Pmel17/gp100 expression in primary human tissue specimens: implications for melanoma immuno- and gene-therapy
S. Wagner (1997)
Apigenin inhibits proliferation of ovarian cancer A2780 cells through Id1
Zhao-dong Li (2009)
Lymphangioleiomyomatosis: a study of 72 patients from the Spanish registry.
E. Antón (2009)
Prognostic significance of cytoplasmic SOX9 in invasive ductal carcinoma and metastatic breast cancer
G. Chakravarty (2011)
The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
Sendurai A Mani (2008)
Models of Breast Morphogenesis Based on Localization of Stem Cells in the Developing Mammary Lobule
G. Honeth (2015)
A six-gene signature predicting breast cancer lung metastasis.
Thomas Landemaine (2008)
Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance
J. Zhou (2007)
The epithelial - mesenchymal transition generates
Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells
C. Li (2014)
Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis*
Koichi Nishiyama (2007)
The LAM cell: what is it, where does it come from, and why does it grow?
G. Finlay (2004)
mTOR: from growth signal integration to cancer, diabetes and ageing
R. Zoncu (2011)
This paper is referenced by
Circulating Lymphangioleiomyomatosis Tumor Cells With Loss of Heterozygosity in the TSC2 Gene Show Increased Aldehyde Dehydrogenase Activity.
G. Pacheco-Rodríguez (2019)
Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway
Jiaxin Kang (2018)
Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model.
H. Prizant (2016)
Study of breast cancer incidence in patients of lymphangioleiomyomatosis
O. Nuñez (2016)
Risk of breast cancer in patients with lymphangioleiomyomatosis.
O. Nuñez (2019)
Correction: Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness
Gorka Ruiz de Garibay (2018)
Expression ratio of the TGFβ-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response
D. Dvornikov (2018)
SOX9: The Master Regulator of Cell Fate in Breast Cancer.
Samir Jana (2020)
Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition
F. Mateo (2017)
Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers
S. Klimov (2017)