Expression of endothelin-1 is related to poor prognosis in non-small cell lung carcinoma.

The endothelin (ET) system influences tumourigenesis and tumour progression by various mechanisms, including angiogenesis. The aim of this study was to determine whether the expression of endothelin-1 (ET-1) is related to the angiogenic phenomenon in lung cancer and whether it could be involved in its clinical behaviour. Expression of ET-1, endothelin-converting enzyme-1 (ECE-1) and endothelin-receptors ETA and ETB was examined in 201 non-small cell lung carcinoma (NSCLC) and corresponding normal tissues using real-time polymerase chain reaction (RT-PCR). Forty NSCLC were also analysed for vascular endothelial growth factor (VEGF) expression by a competitive-PCR approach to assess whether ET-1 expression was related to this angiogenic factor. A higher number of cases with ET-1, ECE-1 and ETA mRNA expression was observed in malignant lung tumours compared with normal lung tissues (45.7% versus 33% for ET-1 (P < 0.0001); 38.3% versus 16.5% for ECE-1 (P = 0.004); and 42.8% versus 28.5% for ETA (P < 0.0001)). On the other hand, ETB mRNA was higher in normal lung tissues than in tumour samples (58.5% versus 52.8% (P < 0.0001)). Immunohistochemical analysis was also performed in 78 cases, selected from among those with high ET-1 mRNA, to confirm the presence of ET-1 protein and to determine its distribution and localisation. Moreover, an interesting relationship was observed between ET-1 and VEGF mRNA levels (P = 0.02). At univariate analysis, clinical-pathological parameters, such as sex, nodal metastatic involvement and stage, and ET-1 expression were seen to be significant predictors of worse prognosis regarding both overall survival (P = 0.001, P = 0.0003, P = 0.001 and P = 0.03, respectively) and disease-free interval (P = 0.0005, P = 0.0007, P = 0.001 and P = 0.04, respectively). We conclude that ET-1 could be involved in angiogenic phenomena in NSCLC and may represent a further indicator of progression and poor prognosis in this type of cancer, with interesting therapeutic implications.

[1]  M. Ogawa,et al.  Prognostic significance of three novel biologic factors in a clinical trial of adjuvant therapy for node-negative breast cancer. , 1995, Surgery.

[2]  L. Kiesel,et al.  Endothelin-1-, Endothelin-A-, and Endothelin-B-Receptor Expression Is Correlated with Vascular Endothelial Growth Factor Expression and Angiogenesis in Breast Cancer , 2004, Clinical Cancer Research.

[3]  G. Burnstock,et al.  Raised endothelin 1 levels in patients with colorectal liver metastases , 1998, The British journal of surgery.

[4]  S. Magnuson,et al.  Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. , 1996, Cancer research.

[5]  M. Yanagisawa,et al.  Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3. , 1991, American journal of human genetics.

[6]  C. Angeletti,et al.  Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas , 1999, British Journal of Cancer.

[7]  R. Plunkett,et al.  Correlation of Endothelin‐1 and Transforming Growth Factor β1 with Malignancy and Vascularity in Human Gliomas , 1997, Journal of neuropathology and experimental neurology.

[8]  M. Ogawa,et al.  A large amount of endothelin-1 is present in human breast cancer tissues. , 1991, Research communications in chemical pathology and pharmacology.

[9]  M. Polokoff,et al.  Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. , 1994, Pharmacological reviews.

[10]  M. Yanagisawa,et al.  Cloning and functional expression of human cDNA for the ETB endothelin receptor. , 1991, Biochemical and biophysical research communications.

[11]  C. Angeletti,et al.  Quantitation by competitive PCR assay of vascular endothelial growth factor in non-small cell lung carcinomas. , 1999, International journal of oncology.

[12]  J. Dřímal,et al.  Enhanced endothelin ETB receptor down-regulation in human tumor cells , 2000 .

[13]  J. Nelson,et al.  Identification of endothelin–1 in the pathophysiology of metastatic adenocarcinoma of the prostate , 1995, Nature Medicine.

[14]  G. Burnstock,et al.  Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ET A receptor antagonism , 2001, British Journal of Cancer.

[15]  E. Levin,et al.  Vasoactive Peptides Modulate Vascular Endothelial Cell Growth Factor Production and Endothelial Cell Proliferation and Invasion* , 1997, The Journal of Biological Chemistry.

[16]  E. Levin.  Mechanisms of disease : endothelins , 1995 .

[17]  P. Natali,et al.  Endothelin receptors as novel targets in tumor therapy , 2004, Journal of Translational Medicine.

[18]  C. Maggi,et al.  Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. , 1995, The American journal of physiology.

[19]  T. Fan,et al.  Endothelin-3 mediated proliferation in wounded human umbilical vein endothelial cells. , 1993, Biochemical and biophysical research communications.

[20]  Max H. Myers,et al.  Manual for Staging of Cancer , 1992 .

[21]  J. Winkles,et al.  Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. , 1994, The Journal of biological chemistry.

[22]  J. Brooks,et al.  Methylation of the 5' CpG island of the endothelin B receptor gene is common in human prostate cancer. , 1997, Cancer research.

[23]  K. Catt,et al.  Activation of mitogenic signaling by endothelin 1 in ovarian carcinoma cells. , 1997, Cancer research.

[24]  Chakrabarti,et al.  Augmented expression of endothelin‐1, endothelin‐3 and the endothelin‐B receptor in breast carcinoma , 2000, Histopathology.

[25]  J. Choudhuri,et al.  Use of viral promoters in mammalian cell-based bioassays: How reliable? , 2004, Journal of Translational Medicine.

[26]  F. Spinella,et al.  Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. , 2001, Cancer research.

[27]  K. Catt,et al.  Autocrine actions of endothelin-1 as a growth factor in human ovarian carcinoma cells. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  D. Rodman,et al.  Role of endothelin-1 in lung disease , 2001, Respiratory research.

[29]  D. Mikhailidis,et al.  Endothelins in the urinary tract , 2000, BJU international.

[30]  S. Magnuson,et al.  Human astrocytoma U138MG cells express predominantly type-A endothelin receptor. , 1996, Biochimica et biophysica acta.

[31]  N. Brière,et al.  Growth regulatory properties of endothelins , 1993, Peptides.

[32]  O. Resta,et al.  Endothelin-1 Is Increased in the Breath Condensate of Patients with Non-Small-Cell Lung Cancer , 2004, Oncology.

[33]  P. Natali,et al.  Role of endothelin-1 in neovascularization of ovarian carcinoma. , 2000, The American journal of pathology.

[34]  N. London,et al.  Endothelin-1 is a novel prognostic factor in non-small cell lung cancer. , 2004, The International journal of biological markers.

[35]  P. Woll,et al.  Studies on the expression of endothelin, its receptor subtypes, and converting enzymes in lung cancer and in human bronchial epithelium. , 2000, American journal of respiratory cell and molecular biology.

[36]  A. Weindl,et al.  Expression and localization of endothelin-1 and endothelin receptors in human meningiomas. Evidence for a role in tumoral growth. , 1995, The Journal of clinical investigation.

[37]  Ivar Giaever,et al.  Permissive Role of Nitric Oxide in Endothelin-induced Migration of Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[38]  L. Kiesel,et al.  Expression of endothelin-1, endothelin-A, and endothelin-B receptor in human breast cancer and correlation with long-term follow-up. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  M. Ogawa,et al.  Abundant expression of immunoreactive endothelin 1 in mammary phyllodes tumor: possible paracrine role of endothelin 1 in the growth of stromal cells in phyllodes tumor. , 1992, Cancer research.

[40]  G. Taraboletti,et al.  Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. , 2000, The American journal of pathology.

[41]  K. Catt,et al.  Endothelins as Autocrine Regulators of Tumor Cell Growth , 1998, Trends in Endocrinology & Metabolism.

[42]  K. Kojima,et al.  Expression of endothelin-1 immunoreactivity in breast cancer. , 1995, Surgical oncology.

[43]  P. Natali,et al.  Expression of endothelin 1 and endothelin A receptor in ovarian carcinoma: evidence for an autocrine role in tumor growth. , 1999, Cancer research.

[44]  D. Ribatti,et al.  Endothelin-1, a Regulator of Angiogenesis in the Chick Chorioallantoic Membrane , 2001, Journal of Vascular Research.

[45]  M. Goligorsky,et al.  CO‐OPERATION BETWEEN ENDOTHELIN AND NITRIC OXIDE IN PROMOTING ENDOTHELIAL CELL MIGRATION AND ANGIOGENESIS , 1999, Clinical and experimental pharmacology & physiology.