[en] Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based treatments and identify patients who could potentially benefit from anti-oestrogen treatments. In this study, we highlight the contribution of lymphatic and blood endothelia in the sex-dependent modulation of lung cancer. The orthotopic graft of syngeneic lung cancer cells into immunocompetent mice showed that lung tumours grow faster in female mice than in males. Moreover, oestradiol (E2) promoted tumour development, increased lymph/angiogenesis and VEGFA and bFGF levels in lung tumours of females through an oestrogen receptor (ER) alpha-dependent pathway. Furthermore, while treatment with ERb antagonist was inefficient, ERa antagonist (MPP) and tamoxifen decreased lung tumour volumes, altered blood and lymphatic vasculature and reduced VEGFA and bFGF levels in females, but not in males. Finally, the quantification of lymphatic and blood vasculature of lung adenocarcinoma biopsies from patients aged between 35 and 55 years revealed more extensive lymphangiogenesis and angiogenesis in tumour samples issued from women than from men. In conclusion, our findings highlight an E2/ERa-dependent modulation of lymphatic and blood vascular components of lung tumour microenvironment. Our study has potential clinical implication in a personalised medicine perspective by pointing to the importance of oestrogen status or supplementation on lung cancer development that should be considered to adapt therapeutic strategies.
Disciplines :
Oncology
Author, co-author :
Dubois, Charline; Université de Liège - ULiège > Sciences biomédicales et précliniques > Laboratoire de biologie des tumeurs et du développement
Rocks, Natacha ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de biologie des tumeurs et du développement
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Primac, Irina ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Gallez, Anne ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tumeurs et du développement
Garcia-Caballero, Melissa
Gérard, Céline; Université de Liège - ULiège > Sciences biomédicales et précliniques > Laboratoire de Biologie des Tumeurs et du Développement
Brouchet, Laurent; Thoracic Surgery Department, University Hospital CHU Toulouse, Toulouse, France
Noël, Agnès ; Université de Liège - ULiège > Sciences biomédicales et précliniques > Laboratoire de biologie des tumeurs et du développement
Lenfant, Françoise; INSERM UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires – I2MC, University of Toulouse III Paul Sabatier, UPS, Toulouse, France
Cataldo, Didier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Labo de biologie des tumeurs et du développement
Pequeux, Christel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Language :
English
Title :
Lymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling
Alitalo A & Detmar M 2012 Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31 4499-4508. (https://doi.org/10.1038/onc.2011.602)
Alitalo K, Tammela T & Petrova TV 2005 Lymphangiogenesis in development and human disease. Nature 438 946-953. (https://doi.org/10.1038/nature04480)
Andersson S, Sundberg M, Pristovsek N, Ibrahim A, Jonsson P, Katona B, Clausson CM, Zieba A, Ramstrom M, Soderberg O, et al. 2017 Insufficient antibody validation challenges oestrogen receptor beta research. Nature Communication 8 15840. (https://doi.org/10.1038/ ncomms15840)
Baik CS & Eaton KD 2012 Estrogen signaling in lung cancer: an opportunity for novel therapy. Cancers 4 969-988. (https://doi.org/10.3390/cancers4040969)
Barton M, Filardo EJ, Lolait SJ, Thomas P, Maggiolini M & Prossnitz ER 2017 Twenty years of the G protein-coupled estrogen receptor GPER: historical and personal perspectives. Journal of Steroid Biochemistry and Molecular Biology 176 4-15. (https://doi.org/10.1016/j.jsbmb.2017.03.021)
Billon-Gales A, Fontaine C, Douin-Echinard V, Delpy L, Berges H, Calippe B, Lenfant F, Laurell H, Guery JC, Gourdy P, et al. 2009 Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice. Circulation 120 2567-2576. (https://doi.org/10.1161/CIRCULATIONAHA.109.898445)
Boese AC, Kim SC, Yin KJ, Lee JP & Hamblin MH 2017 Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. American Journal of Physiology: Heart and Circulatory Physiology 313 H524-H545. (https://doi.org/10.1152/ajpheart.00217.2016)
Bouchardy C, Benhamou S, Schaffar R, Verkooijen HM, Fioretta G, Schubert H, Vinh-Hung V, Soria JC, Vlastos G & Rapiti E 2011 Lung cancer mortality risk among breast cancer patients treated with anti-estrogens. Cancer 117 1288-1295. (https://doi.org/10.1002/cncr.25638)
Brouchet L, Krust A, Dupont S, Chambon P, Bayard F & Arnal JF 2001 Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation 103 423-428. (https://doi.org/10.1161/01.CIR.103.3.423)
Cadranel J, Zalcman G & Sequist L 2011 Genetic profiling and epidermal growth factor receptor-directed therapy in nonsmall cell lung cancer. European Respiratory Society 37 183-193. (https://doi.org/10.1183/09031936.00179409)
Cao R, Ji H, Feng N, Zhang Y, Yang X, Andersson P, Sun Y, Tritsaris K, Hansen AJ, Dissing S, et al. 2012 Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. PNAS 109 15894-15899. (https://doi.org/10.1073/pnas.1208324109)
Chlebowski RT, Wakelee H, Pettinger M, Rohan T, Liu J, Simon M, Tindle H, Messina C, Johnson K, Schwartz A, et al. 2016 Estrogen plus progestin and lung cancer: follow-up of the women's health initiative randomized trial. Clinical Lung Cancer 17 10.e11-17.e11. (https://doi.org/10.1016/j.cllc.2015.09.004)
Chu SC, Hsieh CJ, Wang TF, Hong MK & Chu TY 2017 Antiestrogen use in breast cancer patients reduces the risk of subsequent lung cancer: a population-based study. Cancer Epidemiology 48 22-28. (https://doi.org/10.1016/j.canep.2017.02.010)
Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D'Amore PA, Dana MR, Wiegand SJ & Streilein JW 2004 VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. Journal of Clinical Investigation 113 1040-1050. (https://doi.org/10.1172/JCI20465)
De Palma M, Biziato D & Petrova TV 2017 Microenvironmental regulation of tumour angiogenesis. Nature Reviews Cancer 17 457-474. (https://doi.org/10.1038/nrc.2017.51)
Dieterich LC & Detmar M 2016 Tumor lymphangiogenesis and new drug development. Advanced Drug Delivery Reviews 99 148-160. (https://doi.org/10.1016/j.addr.2015.12.011)
Early Breast Cancer Trialists' Collaborative Group, Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, et al. 2011 Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378 771-784. (https://doi.org/10.1016/S0140-6736(11)60993-8)
Gargett CE, Zaitseva M, Bucak K, Chu S, Fuller PJ & Rogers PA 2002 17beta-Estradiol up-regulates vascular endothelial growth factor receptor-2 expression in human myometrial microvascular endothelial cells: role of estrogen receptor-alpha and -beta. Journal of Clinical Endocrinology and Metabolism 87 4341-4349. (https://doi.org/10.1210/jc.2001-010588)
Garmy-Susini B, Delmas E, Gourdy P, Zhou M, Bossard C, Bugler B, Bayard F, Krust A, Prats AC, Doetschman T, et al. 2004 Role of fibroblast growth factor-2 isoforms in the effect of estradiol on endothelial cell migration and proliferation. Circulation Research 94 1301-1309. (https://doi.org/10.1161/01.RES.0000127719.13255.81)
Gerard C, Gallez A, Dubois C, Drion P, Delahaut P, Quertemont E, Noel A & Pequeux C 2017 Accurate control of 17beta-estradiol long-term release increases reliability and reproducibility of preclinical animal studies. Journal of Mammary Gland Biology and Neoplasia 22 1-11. (https://doi.org/10.1007/s10911-016-9368-1)
Greiser CM, Greiser EM & Doren M 2010 Menopausal hormone therapy and risk of lung cancer-systematic review and meta-analysis. Maturitas 65 198-204. (https://doi.org/10.1016/j.maturitas.2009.11.027)
Guivarc'h E, Buscato M, Guihot AL, Favre J, Vessieres E, Grimaud L, Wakim J, Melhem NJ, Zahreddine R, Adlanmerini M, et al. 2018 Predominant role of nuclear versus membrane estrogen receptor alpha in arterial protection: implications for estrogen receptor alpha modulation in cardiovascular prevention/safety. Journal of the American Heart Association 7 e008950. (https://doi.org/10.1161/JAHA.118.008950)
Hamilton KJ, Hewitt SC, Arao Y & Korach KS 2017 Estrogen hormone biology. Current Topics in Developmental Biology 125 109-146.
Hammoud Z, Tan B, Badve S & Bigsby RM 2008 Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocrine-Related Cancer 15 475-483. (https://doi.org/10.1677/ERC-08-0002)
Hershberger PA, Stabile LP, Kanterewicz B, Rothstein ME, Gubish CT, Land S, Shuai Y, Siegfried JM & Nichols M 2009 Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells. Journal of Steroid Biochemistry and Molecular Biology 116 102-109. (https://doi.org/10.1016/j.jsbmb.2009.05.004)
Jala VR, Radde BN, Haribabu B & Klinge CM 2012 Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer. BMC Cancer 12 624. (https://doi.org/10.1186/1471-2407-12-624)
Jemal A, Miller KD, Ma J, Siegel RL, Fedewa SA, Islami F, Devesa SS & Thun MJ 2018 Higher lung cancer incidence in young women than young men in the United States. New England Journal of Medicine 378 1999-2009. (https://doi.org/10.1056/NEJMoa1715907)
Johnson KE, Forward JA, Tippy MD, Ceglowski JR, El-Husayni S, Kulenthirarajan R, Machlus KR, Mayer EL, Italiano JE Jr & Battinelli EM 2017 Tamoxifen directly inhibits platelet angiogenic potential and platelet-mediated metastasis. Arteriosclerosis, Thrombosis, and Vascular Biology 37 664-674. (https://doi.org/10.1161/ATVBAHA.116.308791)
Katcoff H, Wenzlaff AS & Schwartz AG 2014 Survival in women with NSCLC: the role of reproductive history and hormone use. Journal of Thoracic Oncology 9 355-361. (https://doi.org/10.1097/JTO.0000000000000077)
Kim KH, Young BD & Bender JR 2014 Endothelial estrogen receptor isoforms and cardiovascular disease. Molecular and Cellular Endocrinology 389 65-70. (https://doi.org/10.1016/j.mce.2014.02.001)
Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA & Yanagisawa M 2001 Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Developmental Biology 230 230-242. (https://doi.org/10.1006/dbio.2000.0106)
Lewis DR, Check DP, Caporaso NE, Travis WD & Devesa SS 2014 US lung cancer trends by histologic type. Cancer 120 2883-2892. (https://doi.org/10.1002/cncr.28749)
Liu C, Liao Y, Fan S, Tang H, Jiang Z, Zhou B, Xiong J, Zhou S, Zou M & Wang J 2015 G protein-coupled estrogen receptor (GPER) mediates NSCLC progression induced by 17beta-estradiol (E2) and selective agonist G1. Medical Oncology 32 104. (https://doi.org/10.1007/ s12032-015-0558-2)
Mah V, Seligson DB, Li A, Marquez DC, Wistuba, II, Elshimali Y, Fishbein MC, Chia D, Pietras RJ & Goodglick L 2007 Aromatase expression predicts survival in women with early-stage non small cell lung cancer. Cancer Research 67 10484-10490. (https://doi. org/10.1158/0008-5472.CAN-07-2607)
Mahmoodzadeh S, Leber J, Zhang X, Jaisser F, Messaoudi S, Morano I, Furth PA, Dworatzek E & Regitz-Zagrosek V 2014 Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction. Journal of Cell Science and Therapy 5 153. (https://doi.org/10.4172/2157-7013.1000153)
Morfoisse F, Tatin F, Chaput B, Therville N, Vaysse C, Metivier R, Malloizel-Delaunay J, Pujol F, Godet AC, De Toni F, et al. 2018 Lymphatic vasculature requires estrogen receptor-alpha signaling to protect from lymphedema. Arteriosclerosis, Thrombosis, and Vascular Biology 38 1346-1357. (https://doi.org/10.1161/ATVBAHA.118.310997)
Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF, et al. 2018 Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 21 425-532. (https://doi.org/10.1007/s10456-018-9613-x)
Paupert J, Sounni NE & Noel A 2011 Lymphangiogenesis in post-natal tissue remodeling: lymphatic endothelial cell connection with its environment. Molecular Aspects of Medicine 32 146-158. (https://doi.org/10.1016/j.mam.2011.04.002)
Pequeux C, Raymond-Letron I, Blacher S, Boudou F, Adlanmerini M, Fouque MJ, Rochaix P, Noel A, Foidart JM, Krust A, et al. 2012 Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis. Cancer Research 72 3010-3019. (https://doi.org/10.1158/0008-5472.CAN-11-3768)
Petrova TV & Koh GY 2018 Organ-specific lymphatic vasculature: from development to pathophysiology. Journal of Experimental Medicine 215 35-49. (https://doi.org/10.1084/jem.20171868)
Pietras RJ & Marquez-Garban DC 2007 Membrane-associated estrogen receptor signaling pathways in human cancers. Clinical Cancer Research 13 4672-4676. (https://doi.org/10.1158/1078-0432.CCR-07-1373)
Pietras RJ, Marquez DC, Chen HW, Tsai E, Weinberg O & Fishbein M 2005 Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 70 372-381. (https://doi.org/10.1016/j.steroids.2005.02.017)
Raso MG, Behrens C, Herynk MH, Liu S, Prudkin L, Ozburn NC, Woods DM, Tang X, Mehran RJ, Moran C, et al. 2009 Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clinical Cancer Research 15 5359-5368. (https://doi.org/10.1158/1078-0432.CCR-09-0033)
Rocks N, Bekaert S, Coia I, Paulissen G, Gueders M, Evrard B, Van Heugen JC, Chiap P, Foidart JM, Noel A, et al. 2012 Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer. British Journal of Cancer 107 1083-1092. (https://doi.org/10.1038/bjc.2012.379)
Rodriguez-Lara V, Hernandez-Martinez JM & Arrieta O 2018 Influence of estrogen in non-small cell lung cancer and its clinical implications. Journal of Thoracic Disease 10 482-497. (https://doi.org/10.21037/jtd.2017.12.61)
Rouquette I, Lauwers-Cances V, Allera C, Brouchet L, Milia J, Nicaise Y, Laurent J, Delisle MB, Favre G, Didier A, et al. 2012 Characteristics of lung cancer in women: importance of hormonal and growth factors. Lung Cancer 76 280-285. (https://doi.org/10.1016/j.lungcan.2011.11.023)
Schabath MB, Wu X, Vassilopoulou-Sellin R, Vaporciyan AA & Spitz MR 2004 Hormone replacement therapy and lung cancer risk: a case-control analysis. Clinical Cancer Research 10 113-123. (https:// doi.org/10.1158/1078-0432.CCR-0911-3)
Schleidgen S, Klingler C, Bertram T, Rogowski WH & Marckmann G 2013 What is personalized medicine: sharpening a vague term based on a systematic literature review. BMC Medical Ethics 14 55. (https://doi.org/10.1186/1472-6939-14-55)
Siegfried JM 2001 Women and lung cancer: does oestrogen play a role? Lancet Oncology 2 506-513. (https://doi.org/10.1016/S1470-2045(01)00457-0)
Siegfried JM & Stabile LP 2014 Estrongenic steroid hormones in lung cancer. Seminars in Oncology 41 5-16. (https://doi.org/10.1053/j.seminoncol.2013.12.009)
Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD, Christie N, Finkelstein S & Siegfried JM 2002 Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Research 62 2141-2150.
Stanhewicz AE, Wenner MM & Stachenfeld NS 2018 Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. American Journal of Physiology: Heart and Circulatory Physiology [epub]. (https://doi.org/10.1152/ajpheart.00396.2018)
Suzuma I, Mandai M, Takagi H, Suzuma K, Otani A, Oh H, Kobayashi K & Honda Y 1999 17beta-Estradiol increases VEGF receptor-2 and promotes DNA synthesis in retinal microvascular endothelial cells. Investigative Ophthalmology and Visual Science 40 2122-2129.
Tang H, Liao Y, Zhang C, Chen G, Xu L, Liu Z, Fu S, Yu L & Zhou S 2014 Fulvestrant-mediated inhibition of estrogen receptor signaling slows lung cancer progression. Oncology Research 22 13-20. (https://doi.org/10.3727/096504014X14077751730315)
Townsend EA, Miller VM & Prakash YS 2012 Sex differences and sex steroids in lung health and disease. Endocrine Reviews 33 1-47. (https://doi.org/10.1210/er.2010-0031)
Wakelee HA, Wang W, Schiller JH, Langer CJ, Sandler AB, Belani CP, Johnson DH & Eastern Cooperative Oncology Group 2006 Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594. Journal of Thoracic Oncology 1 441-446. (https://doi.org/10.1016/S1556-0864(15)31609-9)
Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, Holmberg L, Yong LC, Kolonel LN, Gould MK, et al. 2007 Lung cancer incidence in never smokers. Journal of Clinical Oncology 25 472-478. (https://doi.org/10.1200/JCO.2006.07.2983)
Wong BW, Zecchin A, Garcia-Caballero M & Carmeliet P 2018 Emerging concepts in organ-specific lymphatic vessels and metabolic regulation of lymphatic development. Developmental Cell 45 289-301. (https://doi.org/10.1016/j.devcel.2018.03.021)
Zhan P, Wang J, Lv XJ, Wang Q, Qiu LX, Lin XQ, Yu LK & Song Y 2009 Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. Journal of Thoracic Oncology 4 1094-1103. (https://doi.org/10.1097/JTO.0b013e3181a97e31)
Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M & He Y 2010 VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Research 20 1319-1331. (https://doi.org/10.1038/cr.2010.116)
Zhao G, Zhao S, Wang T, Zhang S, Lu K, Yu L & Hou Y 2011 Estrogen receptor beta signaling regulates the progression of Chinese nonsmall cell lung cancer. Journal of Steroid Biochemistry and Molecular Biology 124 47-57. (https://doi.org/10.1016/j.jsbmb.2011.01.006)