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EV-Associated Mirnas As a New Source of Biomarkers in Endometrial, Colorectal and Lung Cancers

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EV-Associated Mirnas As a New Source of Biomarkers in Endometrial, Colorectal and Lung Cancers ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en EV-associated miRNAs as a new source of biomarkers in endometrial, colorectal and lung cancers Doctoral thesis presented by Berta Roman Canal to obtain the degree of Doctor for the Universitat Autònoma de Barcelona (UAB) Doctoral thesis performed at Institut de Recerca Biomèdica de Lleida (IRB Lleida), Institut de Recerca de la Vall d’Hebron (VHIR) and Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), under the supervision of Dr. Xavier Matias-Guiu, Dr. Eva Colás and Dr. David Llobet Thesis affiliated to the Department of Biochemistry and Molecular Biology from the UAB, in the PhD program of Biochemistry, Molecular Biology and Biomedicine, under the tutoring of Dr. Joan Xavier Comella Universitat Autònoma de Barcelona, September 2019 Dr. Xavier Matias-Guiu Dra. Eva Colás Dr. David Llobet (director) (director) (director) Dr. Joan Xavier Comella Berta Roman Canal (tutor) (student) El ritme del cos, la melodia de la ment i l’harmonia de l’ànima creen la simfonia de la vida. B.K.S. Iyengar INDEX TABLE OF CONTENTS INDEX OF FIGURES…………………………………………………...……10 INDEX OF TABLES………………………………………………….………11 ABBREVIATIONS……………………………………………………………12 INTRODUCTION……………………………………………………………..15 1. ENDOMETRIAL CANCER ................................................................ 17 1.1 Epidemiology .............................................................................................. 17 1.2 Risk and Protective factors.......................................................................... 18 1.3 Diagnosis .................................................................................................... 19 1.3.1 Signs and symptoms ............................................................................... 19 1.3.2 Screening ................................................................................................ 20 1.3.3 Diagnostic procedure .............................................................................. 20 1.4 EC classification .......................................................................................... 22 1.4.1 Histological classification ......................................................................... 22 1.4.2 FIGO classification .................................................................................. 23 1.5 Treatment ................................................................................................... 25 1.5.1 Preoperative risk assessment ................................................................. 25 1.5.2 Surgery ................................................................................................... 26 1.5.3 Adjuvant Treatment ................................................................................. 27 2. COLORECTAL CANCER ................................................................. 28 2.1 Epidemiology .............................................................................................. 28 2.2 Risk and Protective factors.......................................................................... 29 2.3 Diagnosis .................................................................................................... 31 2.3.1 Signs and symptoms ............................................................................... 31 2.3.2 Screening ................................................................................................ 31 2.3.3 Diagnostic procedure .............................................................................. 34 2.4 CRC classification ....................................................................................... 37 2.4.1 Histological classification ......................................................................... 37 2.4.2 Staging classification ............................................................................... 38 2.5 Treatment ................................................................................................... 40 2.5.1 Surgery ................................................................................................... 40 2.5.2 Neoadjuvant therapy ............................................................................... 42 2.5.3 Adjuvant therapy ..................................................................................... 43 3. LUNG CANCER ................................................................................ 44 3.1 Epidemiology .............................................................................................. 44 3.2 Risk and Protective factors.......................................................................... 45 3.3 Diagnosis .................................................................................................... 47 3.3.1 Signs and symptoms ............................................................................... 47 3.3.2 Screening ................................................................................................ 48 3.3.3 Diagnostic procedure .............................................................................. 49 3.4 Lung cancer classification ........................................................................... 51 3.4.1 Histological classification ......................................................................... 51 3.4.2 Staging classification ............................................................................... 52 3.5 Treatment ................................................................................................... 55 4. BIOMARKERS .................................................................................. 57 4.1 Biomarker definition .................................................................................... 57 4.2 Tissue biopsy .............................................................................................. 57 4.3 Liquid biopsy, a new source of biomarkers .................................................. 59 4.4 Exosomes ................................................................................................... 60 4.4.1 Definition ................................................................................................. 60 4.4.2 Biological functions of exosomes ............................................................ 62 4.4.3 Isolation and characterization methods ................................................... 65 4.4.4 Exosomes as a source of biomarkers ...................................................... 66 4.5 Exosomal miRNA as a biomarkers in cancer research ................................ 67 OBJECTIVES……………………………………………………………...…69 RESULTS…………………………………………………………………..…73 CHAPTER 1……………………………………………………………………………………………………77 CHAPTER 1……………………………………………………………………………………………………97 CHAPTER 1………………………………………………………………………………………………….115 DISCUSSION………………………………………………………….……139 CONCLUSIONES……………………………………………………..……153 JOURNAL OF PUBLICATIONS……………………………………..……157 BIBLIOGRAPHY……………………………………………………………161 INDEX OF FIGURES Figure 1. New cases and deaths for cancer. Figure 2. Stage distribution and 5-year relative survival rates of EC by stage at diagnosis. Figure 3. Causes of abnormal vaginal bleeding. Figure 4. Clinical examination. (A) Pelvic exam. (B) TVS. Figure 5. FIGO stages. Figure 6. New cases and deaths for cancer. Figure 7. Stage distribution and 5-year relative survival rates of CRC by stage at diagnosis. Figure 8. Stage distribution and 5-year relative survival rates of LC by stage at diagnosis. Figure 9. Risk factors of LC. Figure 10. Graphic illustration of LC stages. Figure 11. Treatment of LC at different stages. Figure 12. Schematic representation of EVs. Figure 13. Overall composition of EVs. Schematic representation of the composition (families of proteins, lipids, and nucleic acids) and membrane orientation of EVs. Figure 14. Biological functions of exosomes. Figure 15. Schematic of EV-based liquid biopsy. Liquid biopsies of tumor components in the blood, including CTC, ctDNA, extracellular RNAs and EVs, can be leveraged to diagnose for tumor. Figure 16. Diagnostic performance of the top-8 differentially expressed miRNAs. INDEX OF TABLES Table 1. Histological classification of the EC. Table 2. FIGO EC staging. Table 3. Surgical treatment based on tumor staging. Table 4. Recommended adjuvant treatment for EC patients. Table 5. Key performance indicators for organized screening with different modalities. Table 6. Common genetic and epigenetic alterations in CRC Table 7. Histological classification of CRC. Table 8. Classification of CRC according to local invasion depth (T stage), lymph node involvement (N stage), and presence of distant metastases (M stage). Table 9. Stage classification of CRC. Table 10. Methods for tissue diagnosis of LC. Table 11. Histological classification of the LC. Table 12. Classification of LC according to local invasion depth (T stage), lymph node involvement (N stage), and presence of distant metastases (M stage). Table
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