SpringerImages - Schematic representation of the genetic events supporting the onset of intestinal metaplasia and the development of invasive cancer. Chronic gastro-oesophageal reflux disease (GORD) induces the transformation of the squamous epithelium into a columnar epithelium. Up-regulation of caudal homeobox genes (CDX2 and CDX1) has a pivotal role in this transformation. Bmp-4 is an additional factor implicated in the acquisition of the intestinal phenotype. Dashed line indicates a putative regulatory mechanism. Loss of heterozygosity at 9p and 17p (p16 and p53 loci, respectively) is believed to drive initial clonal expansion and to impair growth control mechanisms allowing accumulation of other genetic alterations as result of chromosomal instability. Alteration in Wnt, COX2 and E-cadherin pathways further impairs the tumour suppression network and promotes neo-angiogenesis and anchorage independent growth. Ultimately amplification of growth factors receptor (EGFR, erb-B2, met and VEGFR) or overexpression of growth factors (TGFβ, VEGF and HGF) establish a more invasive phenotype

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Fig 1

Schematic representation of the genetic events supporting the onset of intestinal metaplasia and the development of invasive cancer. Chronic gastro-oesophageal reflux disease (GORD) induces the transformation of the squamous epithelium into a columnar epithelium. Up-regulation of caudal homeobox genes (CDX2 and CDX1) has a pivotal role in this transformation. Bmp-4 is an additional factor implicated in the acquisition of the intestinal phenotype. Dashed line indicates a putative regulatory mechanism. Loss of heterozygosity at 9p and 17p (p16 and p53 loci, respectively) is believed to drive initial clonal expansion and to impair growth control mechanisms allowing accumulation of other genetic alterations as result of chromosomal instability. Alteration in Wnt, COX2 and E-cadherin pathways further impairs the tumour suppression network and promotes neo-angiogenesis and anchorage independent growth. Ultimately amplification of growth factors receptor (EGFR, erb-B2, met and VEGFR) or overexpression of growth factors (TGFβ, VEGF and HGF) establish a more invasive phenotype

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The Caudal Homeobox genes (CDX) are credited as master transcriptional regulators governing this process (Fig. 1 ) and their involvement in the development of Barrett’s metaplasia has recently been reviewed (Souza 2008 ).

In light of all these lines of evidence it is possible to envisage a mechanism through which gastro-oesophageal reflux induces Barrett’s metaplasia (Fig. 1 ).

Successive longitudinal clonal ordering studies demonstrated that genetic and epigenetic inactivation of p16 and p53 are among the earliest genetic lesions in Barrett’s carcinogenesis (Fig. 1 ) and precede genomic instability and loss of other tumour suppressors (Barrett et al.

Whichever mechanism underlies the expansion of metaplastic cells, it is accepted that lesions in p16 and p53 genes are among the earliest genetic events in Barrett’s and prepare the ground for a growth advantage and susceptibility to acquire further genetic abnormalities (Fig. 1 ) (Sherr 2004 ).

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