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Bedin, Chiara (2014) Utilizzo di Nanoporous Silica Chip nello studio del profilo peptidico plasmatico: applicazione nello sviluppo e progressione del cancro colorettale. [Tesi di dottorato]

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Abstract (inglese)

Background: To date single tumour molecule identification approach for the protein biomarkers discovery is unabled to unequivocally recognize the cancer, because current tumor biomarkers are also expressed in normal cells. The protein profiling identify a specific pattern of hundred of protein in numerous specimens. Low molecular weight (LMW) proteins/peptides, the fraction less abundant of the biological fluids, seem to contain disease-specific information and correlate to the tissue pathological status. The detection by MS-analysis of low abundant fraction and LMW peptides remains a critical challenge.
Aim: A Nanoporous Silica Chip (NSC) was used to select and purify LMW plasma peptides in samples of colorectal cancer (CRC) patients to study the peptide profiling in association to development and progression of tumour.
Materials and Methods: NSC is a patented prototype of Prof. M Ferrari Labs (Dept. of Nanomedicine of The Methodist Hospital Research Institute, Houston TX). It is a disc of 10 cm of diameter with a superficial nanoporous silica thin film.
A standardized, fast and simple protocol was validated to perform the selection of plasma LMW peptides. 34 health subjects, 27 patients with pre-cancer lesion (adenoma ), 33 patients with early stage of CRC (stage I-II) and 34 patients with late stage of CRC (stage III-IV) was enrolled for this study. MS-analysis by MALDI-TOF instrument was performed on fractionated LMW plasma samples. Data were calibrated, aligned and normalized, and then they were undergone to accurate univariate and multivariate statistical analysis to highlight and identify difference of plasma peptide profile intensity comparing the 4 study group.
Results: Good classification of control group was obtained regard patient group, but poor discrimination was observed between adenoma, early stage CRC and late stage CRC. Consequently, 29 ionic species was differentially expressed in study groups. MALDI-TOF/TOF analysis was identified the aminoacid sequence of several ionic species. All of them were fragment peptide of plasma protein arising to inflammatory response and system of complement. Moreover, peptide fragments of C3f and C4-A/B could be generated from precursor peptide by endopreotease and exoprotease cleavage. A peptide fragment was originated from propeptide of ITIH4 (Inter-?-trypsin inhibitor heavy chain H4). ITIH4 was secreted to liver and it belongs to phase acute proteins involved in inflammatory responses. It may also play a role in liver development and regeneration. Some studies were identified some ITIH4 peptide fragments involved in several pathological status as ischemic stroke, breast, ovarian and prostate cancer.
Conclusions: A fast and simple method was set to perform study with NSC. NSC is a new tool with wide potential application. A deep study of obtained peptide proteolytic pattern was necessary suggesting a colorectal cancer specific proteases and exoprotease activity.

Abstract (italiano)

Background: Per la ricerca di biomarcatori proteici, l’approccio basato sulla identificazione di un singolo marcatore hanno, finora, dimostrato l’incapacità di individuare inequivocabilmente il cancro, in parte perché gli attuali biomarcatori tumorali sono anche espressi nelle cellule normali. Il profilo proteico si basa, invece, sulla rilevazione di pattern identificativo di centinaia di proteine in un alto numero di campioni. Il contenuto informativo più alto sembra risiedere nelle proteine/peptidi a basso peso molecolare (LMW), la frazione meno abbondante nei fluidi biologici, che sembrano rispecchiame meglio gli stati fisiopatologici dei tessuti. Per l’analsi in spettrometrometria di massa e’ necessario selezionare e arrichire questa frazione del plasma.
Scopo: Si è focalizzato sull'utilizzo di un dispositivo nanoporoso (Nanoporous Silica Chip, NSC) per il recupero della frazione a basso peso molecolare da plasma, in campioni di pazienti con cancro colorettale (CRC) a vari stadi di progressione tumorale e sullo studio del relativo profilo peptidico mediante tecnica MALDI-TOF.
Materiale e metodi: NSC è un prototipo creato e brevettato dal Laboratorio del Prof. M. Ferrari (Dip. di Nanomedicina presso The Methodist Hospital Research Institute, Houston, TX, USA) costituito da un supporto in silicone, di circa 10cm, rivestito da un sottile strato di silice con una struttura a nano-pori. È stato necessario lo sviluppo di un protocollo semplice e veloce di frazionamento dei peptidi plasmatici. Il protocollo standardizzato è stato applicato per il frazionamento di campioni di plasma di 34 soggetti sani (controlli), 27 con lesione pre-cancerosa (adenoma) e 33 con CRC a stadio precoce (stadio I-II) e 34 con CRC a stadio tardivo (stadio III-IV). La frazione ottenuta è stata analizzata con spettrometria di massa MALDI-TOF e i dati calibrati, allineati e normalizzati sono stati sottoposti ad attenta e accurata analisi statistica univariata e multivariata con lo scopo di identificare differenze nel profilo peptidico plasmatico nei diversi gruppi di soggetti.
Risultati: Si è ottenuta una buona classificazione dei controlli rispetto ai pazienti, ma una scarsa distinzione tra i gruppi di soggetti con adenoma, CRC con stadio precoce e tardivo. Da tale analisi, si sono individuate alcune specie ioniche rappresentate con diversa intensità nei vari gruppi, che sono state sottoposte a identificazione della sequenza amminoacidica mediante MALDI-TOF/TOF. Sono risultate essere tutte frammenti peptidici di proteine plasmatiche appartenenti alla risposta infiammatoria e al sistema del complemento. In particolare i frammenti peptidici del C3f e C4-A/B sembrano originare dal proprio precursore a seguito di tagli enzimatici a carico di endoproteasi ed esoproteasi. La presenza di alcuni di questi frammenti è risultata essere variabile nei gruppi in esame. Inoltre si è identificato un interessante frammento peptidico che deriva dal propeptide di ITIH4 (Inter-?-trypsin inhibitor heavy chain H4), una proteina di fase acuta secreta dal fegato e coinvolta nello sviluppo e rigerazione epatica. Una ricerca bibliografica ha identificato che frammenti di ITIH4, possono essere possibili biomarcatori per vari stati patologici come infarto e cancro alla mammella e prostata.
Conclusioni: La metodica ottimizzata è semplice e veloce e NSC è un dispositivo con ampie potenzialità di utilizzo. È necessario approfondire lo studio sul particolare pattern proteolitico di peptidi ottenuti, che suggerisce il coinvolgimento di un'attività esoproteasica ben distinta e la presenza di proteasi specifiche del tumore del colon-retto.

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Tipo di EPrint:Tesi di dottorato
Relatore:De Filippis, Cosimo
Correlatore:Agostini, Marco
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE
Data di deposito della tesi:30 Gennaio 2014
Anno di Pubblicazione:30 Gennaio 2014
Parole chiave (italiano / inglese):chip silice nanoporosa; peptidi circolanti; cancro colorettale; maldi-tof nanoporous silica chip; circulating peptide; colorectal cancer; maldi-tof
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:6723
Depositato il:10 Nov 2014 16:37
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