title: Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon.
abstract: BACKGROUND
  The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations.
  
  
  METHODS
  We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa).
  
  
  RESULTS
  Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e.g., those mediated by G proteins and nuclear hormone receptors) involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2>M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e.g., increased aerobic glycolysis, downregulation of pathways that metabolize drugs and xenobiotics).
  
  
  CONCLUSIONS
  Our analysis revealed specific pathways whose dysregulation might play a role in each transition of the transformation process. This is the first study in which such an approach has been used to gain further insights into colorectal tumorigenesis. Therefore, these data provide a launchpad for further exploration of the molecular characterization of colorectal tumorigenesis using systems biology approaches.
authors.affiliation: Istituto di Studi sui Sistemi Intelligenti per l'Automazione - CNR, Via Amendola 122/D-I, 70126 Bari, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Maglietta
authors.forename: Vania Cosma
authors.initials: VC
authors.lastname: Liuzzi
authors.forename: Elisa
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.forename: Teresa
authors.initials: T
authors.lastname: Staiano
authors.forename: Federico
authors.initials: F
authors.lastname: Buffoli
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.forename: Nicola
authors.initials: N
authors.lastname: Ancona
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome