Le cellule staminali embrionali (ES) pluripotenti sono mantenute da un complesso di reti molecolari che coinvolgono un numero limitato di fattori di trascrizione con regolatori epigenetici come i geni Polycomb e Trithorax. Oggi è ampiamente accettato che i tumori derivino dalla trasformazione di cellule staminali adulte (ASC) (teoria cancer stem cell), ma negli ultimi anni alcuni lavori hanno mostrato che i tumori condividono il fenotipo trascrizionale con le cellule staminali embrionali (Visvader J. et al2008). Recentemente Kim ed altri (Kim et al 2010) hanno dimostrato che l’overall ES transcriptional program può essere ulteriormente suddiviso in distinti “moduli”, che coinvolgono reti molecolari parzialmente sovrapposte che sono finemente regolate per funzionare in modo diverso nelle ES, ASC e nei tumori. Questi moduli sono: 1) CORE modulo: include fattori trascrizionali per il mantenimento della pluripotenza come : Oct4, Sox2, ecc; 2) PRC modulo: comprende i geni Polycomb; 3) Myc modulo: include le molecole che interagiscono con c-Myc. Il nostro lavoro si è focalizzato nello studio di come molecole comprese in questi moduli, possono essere differenzialmente regolate per determinare il fenotipo staminale e/o tumorale e in come il profilo di trascrizione può essere efficace nella diagnosi della aggressività del tumore ed eventuale terapia. In questo lavoro abbiamo comparato le ESC, ASC e tumori mammari per il profilo di espressione dei geni che identificano il fenotipo “staminale”. Abbiamo trovato che: 1) ASC presentono un profilo trascrizionale che è intermedio tra le ESC e i tessuti differenziali: 2) ASC mostrano un profilo trascrizionale che è intermedio tra i tumori e i tessuti normali; 3) i tumori al seno più aggressivi (basal-like) overesprimono tutti i tre moduli ES descritti da Kim rispetto a quelli meno aggressivi, anche se solo l’arricchimento del modulo Myc è risultato statisticamente significativo.
Embryonic stem (ES) cells pluripotency is maintained by complex molecular networks that involve limited numbers of transcription factors along with epigenetic regulators, such as Polycomb and Trithorax genes It is currently broadly accepted that tumors may derive from the transformation of adult stem cells (ASC)(cancer stem cell theory), but a few paper in the last two or three years, have been revealing that tumors share the transcriptional phenotype with ES cells (Visvader J. et al 2008). Kim et al (Kim et al 2010) have recently demonstrated that the overall ES transcriptional program can be further divided in distinct “modules”, that involve minimally over-lapping networks and that may be finely regulated to function differently in ES, ASC and tumors. These modules are: 1) CORE module: includes pluripotency transcriptional factors such as Oct4, Sox2, etc..; 2) PRC module: includes polycomb genes; 3) MYC-centered module, including molecules interacting with c-Myc. Our work focused the study of how the molecules comprised in these modules may be differentially regulated to ultimately determine the stem and/or tumor phenotype and whether their transcriptional profile may be effective in diagnosis of tumor aggressiveness and therapy outcome. In this work we have compared ESC, ASC and breast tumors for the expression profile of varied gene sets identifying the “stem” phenotype. We found that: 1) ASC exhibit a transcriptional profile for these genes that is intermediate between that of ESC and that of terminally differentiated tissues; 2) ASC exhibit a transcriptional profile for these genes that is intermediate between that of Tumors and that of normal, terminally differentiated tissues; 3) the most aggressive breast cancers (basal-like intrinsic sub-types) over-expressed all the Kim’s ES modules compared to the less aggressive ones, although only the enrichment of the Myc module resulted statistically significant.
Transcriptional connections between embryonic stem, adult stem and tumor phenotypes
MANNUCCI, Silvia
2012-01-01
Abstract
Embryonic stem (ES) cells pluripotency is maintained by complex molecular networks that involve limited numbers of transcription factors along with epigenetic regulators, such as Polycomb and Trithorax genes It is currently broadly accepted that tumors may derive from the transformation of adult stem cells (ASC)(cancer stem cell theory), but a few paper in the last two or three years, have been revealing that tumors share the transcriptional phenotype with ES cells (Visvader J. et al 2008). Kim et al (Kim et al 2010) have recently demonstrated that the overall ES transcriptional program can be further divided in distinct “modules”, that involve minimally over-lapping networks and that may be finely regulated to function differently in ES, ASC and tumors. These modules are: 1) CORE module: includes pluripotency transcriptional factors such as Oct4, Sox2, etc..; 2) PRC module: includes polycomb genes; 3) MYC-centered module, including molecules interacting with c-Myc. Our work focused the study of how the molecules comprised in these modules may be differentially regulated to ultimately determine the stem and/or tumor phenotype and whether their transcriptional profile may be effective in diagnosis of tumor aggressiveness and therapy outcome. In this work we have compared ESC, ASC and breast tumors for the expression profile of varied gene sets identifying the “stem” phenotype. We found that: 1) ASC exhibit a transcriptional profile for these genes that is intermediate between that of ESC and that of terminally differentiated tissues; 2) ASC exhibit a transcriptional profile for these genes that is intermediate between that of Tumors and that of normal, terminally differentiated tissues; 3) the most aggressive breast cancers (basal-like intrinsic sub-types) over-expressed all the Kim’s ES modules compared to the less aggressive ones, although only the enrichment of the Myc module resulted statistically significant.File | Dimensione | Formato | |
---|---|---|---|
Tesi Dott.ssa Mannucci Silvia.pdf
non disponibili
Tipologia:
Tesi di dottorato
Licenza:
Accesso ristretto
Dimensione
1.98 MB
Formato
Adobe PDF
|
1.98 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.