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Reviewing The Osteotropism In Neuroendocrine Tumors: The Role Of Epithelial-Mesenchymal Transition

M. Cives, Francesca Rizzo, V. Simone, F. Bisceglia, S. Stucci, A. Seeber, G. Spizzo, T. Montrone, L. Resta, F. Silvestris
Published 2015 · Biology, Medicine
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Background: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. Methods: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF-β1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. Results: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-β1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. Conclusion: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization.
This paper references
Nuclear expression of chemokine receptor CXCR4 indicates poorer prognosis in gastric cancer.
Takanobu Masuda (2014)
99mTc-pyrophosphate bone scans in patients with metastatic carcinoid tumors.
Feldman Jm (1977)
10.1309/AJCPIV40ISTBXRAX
Epithelial-mesenchymal transition markers in the differential diagnosis of gastroenteropancreatic neuroendocrine tumors.
José A Galván (2013)
10.1016/S1470-2045(13)70362-0
Recommendations for management of patients with neuroendocrine liver metastases.
A. Frilling (2014)
10.1530/ERC-13-0246
Grading the neuroendocrine tumors of the lung: an evidence-based proposal.
G. Rindi (2014)
10.1097/MPA.0000000000000267
Bone Metastases in Well-to-Moderately Differentiated Neuroendocrine Tumors: A Single Institutional Review From the Ohio State University Medical Center
Juraj Kavecansky (2015)
10.1097/00003086-198805000-00032
Metastatic carcinoid of bone. Report of two cases and review of the literature.
Powell Jm (1988)
10.1038/ncomms2393
MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11.
J. Bockhorn (2013)
10.1242/jcs.111302
Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro
Sonali Sonnylal (2013)
Tyr 3 -Octreotide PET in Comparison to CT and Bone Scintigraphy
D. Putzer (2009)
10.1016/0002-9343(85)90313-4
The carcinoid syndrome: comparison of 21 necropsy subjects with carcinoid heart disease to 15 necropsy subjects without carcinoid heart disease.
E M Ross (1985)
10.1371/journal.pone.0085803
Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer
Weg M Ongkeko (2014)
Trafficking of normal
M Kucia
10.1093/jnci/85.3.200
Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer.
Donald C Allred (1993)
10.1002/ar.22821
The effect of CXCR4 silencing on epithelial-mesenchymal transition related genes in glioma U87 cells.
Y. Zhu (2013)
10.1038/nrc822
Epithelial–mesenchymal transitions in tumour progression
J. Thiery (2002)
10.1159/000151562
Thirteen-Month Registration of Patients with Gastroenteropancreatic Endocrine Tumours in France
Catherine Lombard-Bohas (2008)
10.1517/14712598.2013.843667
Molecular target therapy for bone metastasis: starting a new era with denosumab, a RANKL inhibitor
Christian Rolfo (2014)
10.1016/j.bone.2010.07.023
Epithelial plasticity, cancer stem cells and bone metastasis formation.
Gabri van der Pluijm (2011)
10.1016/S0895-4356(00)00314-0
Adjusting for multiple testing--when and how?
Ralf Bender (2001)
10.1530/EC-14-0119
Bone metastases and skeletal-related events from neuroendocrine tumors
K. Van Loon (2015)
10.1200/JCO.2012.44.5924
Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors.
Jonathan R Strosberg (2013)
10.3892/mmr.2014.2818
TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells
Q. Wang (2015)
99mTc-pyrophosphate bone scans in patients with metastatic carcinoid tumors.
Jerome M. Feldman (1977)
10.1677/ERC-10-0026
Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance.
Gregory A. Kaltsas (2011)
10.1210/jc.2002-021314
Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1.
Fathia Gibril (2003)
10.1159/000329873
The Expression of the Hypoxia Markers CA9 and CXCR4 Is Correlated with Survival in Patients with Neuroendocrine Tumours of the Ileum
L. Deschamps (2011)
10.1200/JCO.2010.33.2056
Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting.
Matthew H. Kulke (2011)
10.1186/1471-2407-14-855
Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors
José A Galván (2013)
Bone metastases in carcinoid tumors: clinical features, imaging characteristics, and markers of bone metabolism.
Wim G. Meijer (2003)
10.3928/0147-7447-19920501-10
Evaluation, prognosis, and medical treatment considerations of metastatic bone tumors.
Michael E. Brage (1992)
metastasis formation
R Derynck (2011)
Cysteine ( C )-XC Receptor 4 Undergoes Transportin 1-Dependent Nuclear Localization and Remains Functional at the Nucleus of Metastatic Prostate Cancer Cells
Ayesha S. Don-Salu-Hewage (2013)
10.1136/jclinpath-2013-201932
Expression of EpCAMMF and EpCAMMT variants in human carcinomas
Dominic Fong (2014)
10.1677/ERC-09-0085
Hypoxia stimulates CXCR4 signalling in ileal carcinoids.
Y. Arvidsson (2010)
10.1016/j.ecl.2010.12.005
The epidemiology of gastroenteropancreatic neuroendocrine tumors.
Ben G. Lawrence (2011)
10.1159/000355612
Clinical and Prognostic Features of Rectal Neuroendocrine Tumors
Brett M. Weinstock (2013)
10.1016/j.ccell.2014.11.025
14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.
J. Xu (2015)
10.1111/his.12307
Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer.
Dominic Fong (2014)
10.3390/cancers4010281
Epithelial-Mesenchymal Transition Is a Critical Step in Tumorgenesis of Pancreatic Neuroendocrine Tumors
Volker Fendrich (2012)
10.1245/s10434-010-0985-4
The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the Future of TNM
Stephen B Edge (2010)
10.1007/s10555-013-9488-7
RANK-mediated signaling network and cancer metastasis
Gina Chia-Yi Chu (2013)
Saeteurn KY: Signaling pathway cooperation in TGF-βinduced epithelial-mesenchymal transition
R Derynck (2014)
TGFbeta signaling in growth control, cancer, and heritable disorders.
Joan Massagué (2000)
10.1023/A:1008215730767
Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center.
Eva Tiensuu Janson (1997)
[Neuroendocrine neoplasms of the digestive system].
J A Sulbarán Muñoz (1990)
10.3892/OR_00000572
CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma.
Linhui Wang (2009)
10.1002/cncr.20659
Carcinoid metastasis to the brain.
R. Hlatký (2004)
10.1097/00006231-200208000-00006
Evaluation of 111In-pentetreotide, 131I-MIBG and bone scintigraphy in the detection and clinical management of bone metastases in carcinoid disease
Johanna Maria Zuetenhorst (2002)
10.1007/s00018-014-1693-1
Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences
Olivier Gires (2014)
10.1159/000197899
Survival and Prognostic Factor Analysis of 146 Metastatic Neuroendocrine Tumors of the Mid-Gut
Jonathan R Strosberg (2009)
10.1016/S1535-6108(03)00132-6
A multigenic program mediating breast cancer metastasis to bone.
Y. Kang (2003)
10.3892/OL.2012.622
Skeletal metastasis of carcinoid tumors: Two case reports and review of the literature.
Takeshi Hori (2012)
10.1038/ncb2976
Oncogenic roles of EMT-inducing transcription factors
Alain Puisieux (2014)
10.1038/sj.onc.1207097
Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells
M. Burger (2003)
10.1016/j.ceb.2014.09.001
Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition.
Rik Derynck (2014)
10.1159/000051856
Natural History of Neuroendocrine Enteropancreatic Tumors
M. Mignon (2000)
10.3748/WJG.V13.I39.5208
CTGF, intestinal stellate cells and carcinoid fibrogenesis.
M. Kidd (2007)
10.1634/stemcells.2004-0342
Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis.
Magdalena J Kucia (2005)
10.1007/s00330-012-2615-y
Carcinoid tumours: predicting the location of the primary neoplasm based on the sites of metastases
Praveen Bhosale (2012)
10.1016/S1470-2045(07)70410-2
Gastroenteropancreatic neuroendocrine tumours.
Irvin Mark Modlin (2008)
10.1016/j.bone.2010.08.004
TGF-β in cancer and bone: implications for treatment of bone metastases.
Patricia López Juárez (2011)
10.1102/1470-7330.2013.0007
Staging of neuroendocrine tumours: comparison of [68Ga]DOTATOC multiphase PET/CT and whole-body MRI
Christina Schraml (2013)
10.1371/journal.pone.0057194
Cysteine (C)-X-C Receptor 4 Undergoes Transportin 1-Dependent Nuclear Localization and Remains Functional at the Nucleus of Metastatic Prostate Cancer Cells
Ayesha S. Don-Salu-Hewage (2013)
and metastasis of cancer stem cells involve similar mechanisms : pivotal role of the SDF - 1 - CXCR 4 axis
I Nevo (2005)
10.1158/1541-7786.MCR-12-0274
Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma
Geertje van der Horst (2012)
10.1677/ERC-07-0108
Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum.
Volker Fendrich (2007)
Recruit - ment of mesenchymal stem cells into prostate tumours promotes metastasis
Y Zhu (2013)
10.1371/journal.pone.0002633
Systematic Evaluation of Candidate Blood Markers for Detecting Ovarian Cancer
C. Palmer (2008)
10.6004/JNCCN.2014.0196
NCCN bone health task force: key recommendations.
Azeez Farooki (2014)
: implications for treatment of bone metastases
S Sonnylal (2011)
10.1159/000335597
ENETS Consensus Guidelines for the Management of Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary
Marianne E. Pavel (2011)
Metastatic carcinoid presenting as a spinal tumor.
Douglas B. Kirkpatrick (1975)
10.1159/000287255
ENETS Consensus Guidelines for the Management of Bone and Lung Metastases from Neuroendocrine Tumors
Beata Kos-Kudła (2010)
Metastatic carcinoid of bone. Report of two cases and review of the literature.
J M Powell (1988)
10.3109/1354750X.2012.745166
Assessment and clinical implications of RANK/RANKL/OPG pathway as markers of bone tumor progression in patients with NET harboring bone metastases
Francesco Ferro Milone (2013)
10.1016/j.imlet.2003.10.019
The tumor microenvironment: CXCR4 is associated with distinct protein expression patterns in neuroblastoma cells.
I. Nevo (2004)



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