Experimental Models of Prostate Cancer Bone Metastasis - Establishment, Characterization and Imaging of Xenograft Bone Metastasis Models

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Experimental Models of Prostate Cancer Bone Metastasis - Establishment, Characterization and Imaging of Xenograft Bone Metastasis Models Experimental Models of Prostate Cancer Bone Metastasis - Establishment, characterization and imaging of xenograft bone metastasis models - PhD thesis presented by Marta Garcia López To obtain the degree of PhD for the Universitat Autònoma de Barcelona (UAB) PhD thesis done at the Research Unit in Biomedicine and Translational and Pediatrics Oncology, at the Vall d’Hebron Research Institute, Vall d’Hebron Hospital, under the supervision of Drs. Jaume Reventós i Puigjaner, Andreas Doll and Juan Morote Robles Doctoral study in Biochemistry, Molecular Biology and Biomedicine. Universitat Autònoma de Barcelona, Faculty of Bioscience, Department of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, 2013 Dr. Jaume Reventós Puigjaner Dr. Andreas Doll Dr. Juan Morote Robles Marta Garcia López No entiendes realmente algo a menos que seas capaz de explicárselo a tu abuela. Albert Einstein Summary In industrialized countries, prostate cancer (PCa) is the most common malignancy in men, but mortality rates are much lower than those recorded in developing countries, reflecting benefits from advances in early diagnosis and effective treatment. However, the metastatic disease rather than the primary tumour is responsible for much of the resulting morbidity and mortality. Skeletal metastases occur in more than 70% of cases of late-stage of PCa and they confer a high level of morbidity, a 5-year survival rate of 25% and median survival of approximately 40 months. Though fractures and spinal cord compression are potential complications, the most common symptom of bone metastases is pain. Bone metastases from PCa lead to an accelerated bone turnover state that features pathological activation of both osteoblasts and osteoclasts. Raised activation of osteoclasts is directly correlated with an increased incidence of skeletal complications, cancer progression and death. Further, once tumour metastasizes to bone, the metastatic disease become incurable and current therapies are palliative and mostly target either tumour cells or osteoclasts. Thus, to better understand the biology of PCa bone metastasis and to investigate new therapy options it is crucial to develop new animal models. In this thesis, we have established new experimental models of PCa bone metastasis by intraosseous (i.o.), intracardiac (i.c.) or intratibial (i.t.) inoculation of human PCa cells in immunodeficient mice. Extensive bone metastasis were monitored by in vivo bioluminescence imaging. Different strategies were performed to describe new molecular targets involved in the mechanisms of PCa bone metastasis and to make a suitable model for evaluating novel compounds as future therapeutic approaches. To conclude, these models provide a reliable reproduction of the clinical situation and allows characterization and design effective treatments by better understanding the molecular mechanisms of PCa bone metastasis. Resum En païssos industrialitzats, el càncer de pròstata (CP) és la neoplasia més comunment diagnosticada en homes i la segona causa de mort relacionada amb càncer, donat que els nivells de mortalitat en aquesta població són molt més baixos que els que es troben en els païssos en desenvolupament, es veu un clar benefici en els avenços tant en el diagnòstic precoç com el desenvolupament de teràpies eficients. No obstant, la disseminació metastàtica més que el tumour primari en sí és la responsable dels problemes de mortalitat i morbiditat associats al CP. Les metàstasis esquelètiques estan presents en més d’un 70% dels casos de CP avançat i confereixen alts nivells de morbiditat, un 25% de supervivència als 5 anys i una mitjana de supervivència de 40 mesos després de ser diagnosticats. Tot i que les fractures patològiques i la compressió de la columna vertebral són les complicacions més probables pel pacient metastàtic, el major símptoma és el dolor. Les metàstasis òssies del CP comporten un estat d’acceleració de la remodelació òssia que es caracteritza per una activació patològica tant dels osteoblasts com dels osteoclasts. Aquesta elevada activació dels osteoclasts està directament correlacionada amb un increment en la incidència de les complicacions òssies, de la progressió tumoural i la mort. A més, una vegada el tumour metastatitza a os, la malaltia esdevé incurable i les teràpies actuals són solament pal·liatives i principalment es dirigeixen a les cèl·lules tumourals o als osteoclasts. Per tant, per entendre millor la biologia de les metàstasis òssies del PC i poder investigar noves teràpies és important desenvolupar nous models animals. En aquesta tesi, s’han establert nous models experimentals de metàstasis del CP mitjançant la inoculació de cèl·lules humanes en ratolins immunodeficients per diferents vies, intraòssia, intracardíaca o intratibial. Finalment, diferents estratègies s’han dut a terme per descriure noves dianes moleculars involucrades en el mecanisme de les metàstasis i poder desenvolupar un model adequat per la evaluació de possibles compostos candidats a ser futures aproximacions terapèutiques. Per concloure, aquests models proporcionen una fiable reproducció de la situació clínica i permeten tant la caracterització com el diseny de tractaments efectibles per compendre millor els mecanismes moleculars de les metàstasis òssies del CP. Acknowledgements “Començaré pels agraïments que segurament serà el més senzill” vaig pensar el dia que vaig decidir escriure la tesi...mentida! És igual o més complicat que la resta ja que no m’agradaria deixar-me a ningú per agrair la seva aportació ni tampoc vull agrair de més. Seré formal i començaré pels meus directors de tesi. Gràcies per donar-me l’oportunitat de continuar amb la meva formació després de la universitat i poder continuar creixent professionalment per tal d’ésser ‘doctora’, un concepte molt allunyat del meu entorn ja que ningú de la meva família i/o amics posseeix aquest títol. Ja m’imaginava que el doctorat no seria un camí de roses però tampoc pensava que en certes ocasions costaria sang, suor i llàgrimes. Com va dir Frances Ashcroft, una reconeguda geneticista i fisiològa britànica, ‘la ciència és un 90% de sang, suor i moltes llàmigres’. Lo de sang ho podríem escriure entre cometes però suor i llàgrimes, no se’n salva. Per proximitat al bloc anterior continuarem amb la gent del laboratori. Gràcies pels consells, idees, aportacions laborals però també per les rialles, les bones estones passades i la empatia entre nosaltres. No nombraré a tothom perquè cadascú sap en quina mesura ha estat allà on havia d’estar en el moment adequat. El agraïment és tant per la gent que encara és al laboratori però també per tots aquells que ja han marxat (Jordi, Hafid, Anna M., ...). Només un petit esment que crec que és imprescindible i és per la Núria, moltes gràcies per tot, per haver-me fet costat, per la teva simpatia i afecte, i per les mil hores de conversa que hem tingut tant al lab com a fora del lab, però sobretot gràcies per la amistat que ha sorgit entre nosaltres i per la tendresa amb la que veus a la Martina. Ampliant el radi però sense sortir de la Vall Hebron, li vull agrair el seu suport a la Yolanda per totes les hores que m’ha dedicat i els bons consells que m’ha proporcionat. Extraoficialment, també li vull agrair les bones estones del cafè i per aguantar-me durant tres dies de congrés per París. Sense anar-me’n massa més lluny, voldria agrair a la gent del estabulari (veterinaris i tècnics) la seva paciència i tolerància així com a la gent de la UCTs (Ricardo, Àlex, Marta, Paqui, Mª Àngeles, Rosa, ...) els favors i no tan favors que m’han fet durant tota la meva estada a la Vall Hebron i per la dedicació que han tingut amb mi. Un record especial també pel Servei de Protèomica. No em puc oblidar a la gent d’Anatomia Patològica que sempre han trobat un forat enmig de la seva feina i estrès per atendre els meus “pernilets” dels ratolins com solia dir en Pere Huguet. Desplaçant-nos cap a l’edifici de Traumatologia, trobem en Roberto, gran company, amic i doctor. El seu paper en aquesta tesi ha estat clau i complicat ja que ha hagut de complir amb els tres rols mencionats però la veritat que ho ha complert amb escreixos. Gracias Roberto por tus ánimos para que siguiera adelante con la tesis y por tu interés en que las cosas salieran siempre lo mejor posible. Muy poca gente tan poco desvinculada del proyecto como tú se hubiera involucrado tanto como lo has hecho. Una mica més lluny però per això no menys important trobem la gent del laboratori del IRB-PCB dirigit pel Roger Gomis, més concretament vull agrair la seva feina, dedicació i temps al Roger i al Marc, tot i que tothom del IRB ha contribuït en la seva mesura. Al Marc li cal una menció especial ja que no només ha col·laborat colze amb colze amb el projecte, sinó que a més ha tingut una contribució emocional, sempre amb el seu bon caràcter i positivisme. També m’agradaria agrair al Sergi L. i al Xavier el seu interès i esforç sobretot en aquest últim tram de la tesi. Gràcies per entendre des d’un principi el que voliem, pel munt d’hores que hi heu dedicat i per fer que fos tan senzill treballar amb vosaltres. Ja fora del àmbit laboral, vull agrair el suport dels meus amics i amigues. Gràcies per fer-me veure que hi ha vida fora del laboratori igual d’acceptable. La meva família també requereix una atenció especial, sobretot els meus pares i el meu germà que sempre han estat allà preguntant per “com va allò que fas tu?”,“què tal estan els teus ratolins?” i escoltant estoicament seminaris i problemes que m’he anat trobant al llarg d’aquests cinc anys sense entendre ni fava. Per últim, no em puc deixar de nombrar la persona més especial i important per a mi, sense la qual mai m’hagués engrescat a fer un doctorat.
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