Saturday, July 23, 2011

Molecular dissection of Barrett’s esophagus

Barrett's esophagus is a disorder in which the lining of the esophagus (the tube that carries food from the throat to the stomach) is damaged by stomach acid.

When one eats, food passes from the throat to the stomach through the esophagus (also called the food pipe or swallowing tube). Once food is in the stomach, a ring of muscles keeps it from leaking backward into the esophagus. If these muscles do not close tightly, stomach acid can leak back into the esophagus. This is called reflux or gastroesophageal reflux. This reflux may cause symptoms of heartburn. It may also damage the lining of the esophagus, which is referred to as Barrett's esophagus.

Barrett's esophagus occurs more often in men than women. A person is at risk for this condition if he/she has had Gastroesophageal reflux disease (GERD) for a long time. Patients with Barrett's esophagus may develop more changes in the esophagus called dysplasia. When dysplasia is present, the risk of getting cancer of the esophagus increases; however, its underlying mechanisms have been debated. Esophageal and gastric adenocarcinoma together kill more than a million people each year in United States alone. Both cancers arise in association with chronic inflammation and are preceded by robust metaplasia with intestinal cell characteristics. Gastric intestinal metaplasia is linked to H. pylori infection, whereas Barrett’s metaplasia of the esophagus can be triggered by GERD. Although H. pylori suppression therapies have contributed to the recent decline of gastric adenocarcinoma, the incidence of esophageal adenocarcinoma, especially in the West, has increased dramatically in the past several decades. Treatments for late stages of these diseases are challenging and largely palliative, therefore considerable efforts have focused on understanding the earlier, precancerous stages of these diseases as a prerequisite to developing therapeutic approaches.    

A recent thought-provoking paper by Wang et al. (June 2011 issue of Cell) tried to elucidate the underlying mechanism of Barrett’s esophagus by focusing on two important points:  1) the function of the transcription factor p63 in epithelial tissue and, 2) the processes involved in epithelial metaplasia. p63 mainly functions in development and it is required for establishing stratified epithelia
(i.e., epithelia with more than one layer of cells) or in other words, p63 is required for the switch from the differentiation program of simple, monolayer epithelia to that of stratified, multilayerepithelia. Thus, without p63, the transition between the two tissue types fails to occur.



Metaplasia, a term originally derived from the greek (means ‘‘something formed’’), is used in medicine to refer to the conversion of one tissue, after it is formed, into another. Most frequently, metaplasia involves neighboring tissues of the same origin (e.g., epithelial or mesenchymal), suggesting that the process involves either discrete genetic/epigenetic changes or a neighboring cell population encroaching on another population’s territory. Nevertheless, the cells of origin for a metaplastic process, regardless of tissue type, remain elusive. Complicating matters are other processes that appear similar to metaplasia, such as the abnormal presence or persistence of ectopic tissues during development. Interestingly, even without metaplasia, zones of transition between simple and stratified epithelia are important sites of cancer development, raising the possibility that these sites contain reservoirs of cells with high transformation potential.

Barrett’s esophagus is an intensely studied form of epithelial metaplasia associated with a high predisposition to cancer. The condition is likely triggered by gastroesophageal reflux and chronic inflammatory conditions and is defined as the replacement of a normally stratified squamous epithelium with a simple columnar epithelium. In many cases, but not all, are normally composed of a stratified epithelium in the upper one-third and a columnar epithelium in the lower two thirds. The findings of Wang et al. are in favor of a model of cell migration, but with an interesting twist. They propose that the cells of origin of Barrett’s esophagus are a group of ‘‘primitive’’ epithelial cells, which are found in the developing esophagus and upper stomach region during embryogenesis but persist at the squamous-columnar cell junction in the adult esophagus.



Figure . p63’s Possible Involvement in Barrett’s Esophagus: )
                                                             (source: Karine Lefort and G. Paolo Dotto's  preview article in June 2011 issue of Cell
(A) The transcription factor p63 has two possible functions in epithelial cell fate commitment and tissue homeostasis: (1) p63 expression helps trigger a transition from a simple, monolayer epithelial lineage to a stratified, multilayer lineage; (2) p63 expression is required for self-renewal of cells in the basal proliferative compartment of stratified epithelia.

(B) The two current models for the underlying mechanism of Barrett’s esophagus are as follows: (1) the epithelial metaplasia results from the reprogramming of progenitor/stem cell populations from the stratified toward simple epithelial lineage; (2) cells giving rise to one compartment migrate to another
compartment.

(C) Now Wang et al. (2011) propose another possible mechanism underlying Barrett’s esophagus. ‘‘Primitive epithelial cells,’’ which originate in embryonic tissue, migrate and replace damaged squamous cells in the adult esophagus.


Wang’s model presented here models the evolution of a Barrett’s-like metaplasia in both embryonic and adult mice from precursor cells that are associated by lineage. The mechanisms by which these metaplasias arise in embryos and adults are remarkably similar and suggest a fundamentally novel evolution of precursors of certain cancers in which the earliest events depend not on genetic changes but rather on competition between cell lineages for access to basement membrane essential for proliferation. If Wang’s model turns out to be true, it would change the classic view of metaplasia, shifting the focus of attention from ‘‘after’’ to ‘‘before the fact.’’

1 comment:

  1. Cancer is a complex set of diseases. Each cancer is unique in the way it grows and develops, its chances of spreading depends on the way it affects one`s body and the symptoms one may experience . Several factors, including location and how the cancerous cells appear under the microscope, determine how cancer is diagnosed. Cancer treatment in India




    ReplyDelete