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Contribution of the integrative pathology to the discovery of biomarkers for non-small cell lung cancer : integrative pathology and lung cancer

Identifieur interne : 000040 ( Hal/Curation ); précédent : 000039; suivant : 000041

Contribution of the integrative pathology to the discovery of biomarkers for non-small cell lung cancer : integrative pathology and lung cancer

Auteurs : Marius Ionut Ilie [France]

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RBID : Hal:tel-00874504

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Abstract

The non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the world. Reliable and validated biomarkers could represent a possible breakthrough in the management of this tumour type, by facilitating diagnosis, refining prognosis and providing guidance towards the choice of the most appropriate therapy. In this thesis we approach the field of NSCLC biomarkers by exploring several aspects related to carcinogenesis and tumour progression. First, we have demonstrated a dual impact of two proteins activated by hypoxia, carbonic anhydrases IX and XII, on the outcome of NSCLC patients. We have demonstrated that high tissue and plasma CAIX expression may be a biomarker of poor prognosis and early relapse in NSCLC patients, whereas the CAXII tissue expression would be predictive of a favourable evolution. In addition, we have shown that dynamic reoxygenation of tumours would be at the origin of this antagonism. Furthermore, the cellular component of the tumour microenvironment has been studied and more particularly we have demonstrated that recruitment by the tumour cells of a subpopulation of neutrophils expressing a specific marker CD66b could have a positive signal during tumour progression of NSCLC. Thirdly, the blood compartment has been evaluated in relationship with the evolution of tumours and in particular we have demonstrated the major diagnostic and prognostic value of circulating tumour cells (CTCs) in patients with NSCLC. Finally, the CTC seem to represent the ideal tool for the detection of biomarkers theranostic in the NCPC. In conclusions, the works presented in this thesis explore possibilities and limitations of biomarker research in NSCLC, highlighting the importance of the quality of the samples and of the accuracy and completeness of clinical data in order to obtain reproducible results.

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<abstract xml:lang="fr">Le cancer pulmonaire non à petites cellules (CNPC) est la première cause de décès par cancer dans le monde. Ce cancer est souvent découvert tardivement, il est agressif, et il est chimio-résistant. La découverte de biomarqueurs pourraient représenter une percée majeure pour la prise en charge de ces patients, en facilitant le diagnostic, le pronostic et orienter vers le choix du traitement le plus approprié. Nous avons exploré plusieurs aspects liés à la progression tumorale dans le but d’identifier de nouveaux biomarqueurs dans les CNPC. Nous avons démontré un impact antagoniste sur l’évolution des CNPC des anhydrases carboniques IX et XII, induites par l’hypoxie tumorale. Une forte expression tissulaire et plasmatique de CAIX est un biomarqueur de mauvais pronostic chez les patients présentant un CNPC, tandis que l’expression tissulaire de CAXII serait prédictive d’une évolution favorable. De plus, nous avons montré que la réoxygénation dynamique des tumeurs serait à l’origine de cet antagonisme. Deuxièmement, la composante cellulaire du microenvironnement tumoral a été étudiée et plus particulièrement nous avons démontré qu’un recrutement par les cellules tumorales des neutrophiles exprimant un marqueur spécifique CD66b pourrait avoir un signal positif au cours de la progression tumorale des CNPC. Troisièmement, le compartiment sanguin a été évalué en relation avec l’évolution des tumeurs et plus particulièrement nous avons démontré la valeur majeure diagnostique et pronostique des cellules tumorales circulantes (CTC) chez les patients atteints d’un CNPC. Enfin, les CTC semblent représenter également le support idéal pour la mise en évidence de biomarqueurs théranostiques dans les CNPC. En conclusion, ces travaux explorent les possibilités et les limites de l’identification de biomarqueurs, en soulignant l'importance de la qualité des échantillons et de l'exactitude et l'exhaustivité des données cliniques afin d'obtenir des résultats reproductibles.</abstract>
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