Elsevier

The Lancet

Volume 360, Issue 9345, 16 November 2002, Pages 1587-1589
The Lancet

Rapid Review
Hallmarks of cancer progression in Barrett's oesophagus

https://doi.org/10.1016/S0140-6736(02)11569-8Get rights and content

Section snippets

Cell cycle

Genetic changes that favour proliferation often affect the cell cycle. The cell cycle is divided into: G1 (first gap), S (DNA synthesis), G2 (second gap), and M (mitosis) (figure 2). Late in G1, cells reach a key restriction point at which they either enter S phase and complete the cycle, or exit and become quiescent (G0). Retinoblastoma protein (Rb) appears to be the molecular switch that controls the restriction point. Hypophosphorylated (active) Rb normally blocks progression, whereas

Growth self-sufficiency

Normal cells require exogenous growth signals to move out of G0 and progress through the restriction point. Growth-signaling molecules, such as hormones, growth factors, and cytokines, bind to transmembrane receptors on the cell surface. The activated receptors communicate with the cell-cycle machinery in the nucleus through pathways involving activation of progrowth regulatory molecules (cyclins). Cyclin D1 normally complexes with cyclin-dependent kinase 4 (CDK4) and cyclin E with Cdk2. These

Ignore antigrowth signals

Antigrowth signals can block cell proliferation by forcing transient entry into quiescence or by inducing a permanent growth arrest characterised by differentiation. Most anti-proliferative signals converge on the Rb pathway. Tumour cells can inactivate tumour-suppressor genes like Rb through various mechanisms, including mutation, deletion of the chromosomal region that harbours the tumour-suppressor allele (loss of heterozygosity [LOH]), or through the attachment of methyl groups to the

Avoidance of apoptosis

Mutations that enable cells to grow autonomously may also trigger apoptosis.11 The apoptotic machinery comprises several death-commitment signaling pathways, activated by DNA damage and other insults which activate apoptosis through a caspase-signaling cascade. One mechanism whereby cancer cells might avoid apoptosis is by interfering with agents, like p53 and 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which normally activate apoptosis. DNA damage results in the rapid accumulation of p53

Limitless replicative potential

To become immortal, cancer cells must subvert the intrinsic mechanisms that limit the proliferative capacity of normal cells. In almost all human cancers, this subversion is achieved through the stabilisation of telomere length via the expression of telomerase. Telomeres are long stretches of non-coding DNA repeats that protect the chromosome ends from degradation and aberrant fusion. The DNA replication machinery cannot copy completely the 3′ ends of chromosomes and 50–200 basepairs of

Sustained angiogenesis

The development of new blood vessels (angiogenesis) is essential for the development, progression, and metastasis of malignant tumours. The vascular endothelial growth factors (VEGFs) are a family of potent angiogenic growth factors that stimulate endothelial cell proliferation and migration, and many human tumours sustain angiogenesis by increasing the expression of VEGFs.23 VEGF is expressed in endothelial and epithelial cells from Barrett's adenocarcinomas and surrounding dysplastic tissues.

Invasion and metastasis

Although the mechanisms whereby cancer cells become invasive and metastasise are poorly understood, abnormalities in cell-cell adhesion molecules (CAMs) play an important role. CAMs such as the cadherin glycoproteins normally function as the glue that holds cells together and as important mediators of cell-cell interactions. E-cadherin, on the surface of all epithelial cells, is linked to the actin cytoskeleton through interactions with catenins in the cytoplasm. Thus anchored to the

Aneuploidy

Some of the same genetic abnormalities above also cause the histological abnormalities that comprise dysplasia as well as aneuploidy. Aneuploidy does not correlate with any single mutation, but reflects widespread DNA changes due to genomic instability.28 Over 90% of high- grade dysplasias and adenocarcinomas in Barrett's oesophagus are aneuploid.29 Aneuploidy has been detected in specialised intestinal metaplasia without dysplasia, and may be a better marker for malignant predisposition than

Conclusion

Many genetic alterations affecting the six cancer hallmarks have been demonstrated during the transition from metaplasia to cancer in Barrett's oesophagus. These cancer hallmarks provide a framework for categorising new genetic abnormalities and for further understanding the genetic events that underlie oesophageal carcinogenesis.

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