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Barrett’s Esophagus which are related to an intestinal phenotype. [27]
Furthermore, BMP4 shifts the gene expression profi le
BE is defi ned by American Gastroenterological of normal squamous cells into columnar cells. Because
Association as “BE is the condition in which any extent cytokeratin (CK) is a major cytoskeleton molecule,
of metaplastic columnar epithelium that predisposes to it can be regarded as a representative phenotype of
cancer development replaces the stratifi ed squamous certain cells. CK 13/14 expressions are highly expressed
[10]
epithelium that normally lines the distal esophagus.” in squamous cells, whereas CK 7, 8, 18, and 20
This means a specialized columnar epithelium expressions elevated in BE epithelium. [28] It has been
characterized by columnar cells, goblet cells, and a shown that expression of SOX9, but not CDX2 or
villous-like structure. [11,12] However, another classifi cation BMP4, induces squamous epithelial cells formation
includes two types of BE. One is “junctional or cardiac toward columnar-like epithelium with expression of
type,” consisting of the predominantly foveolar surface CK 8. [29] SHH/BMP signaling were also activated in
containing mucous glands and resembling cardiac a mouse model with interleukin-1β overexpression.
mucous glands. Another one is “gastric-fundic type,” After one year of continuous infl ammation, intestinal
containing both parietal and chief cells with atrophic metaplasia occurred at the SCJ, and the gene expression
fundic glands. [11-13] Thus, the histological defi nition of BE pattern of those metaplastic cells was similar to those in
remains controversial.
human BE. [30]
The cell of origin of BE has not yet been elucidated. Six Recent advances of next-generation sequencing have
cell types are currently considered as potential origins, provided the opportunity to elucidate genetic alterations
including transdifferentiation of esophageal squamous such as single nucleotide polymorphisms (SNPs).
cells, gastric cardia cells, esophageal submucosal The association between SNPs and BE has been
[15]
[14]
gland cells, esophageal progenitor cells, circulating clarifi ed. It has been reported that chromosomes
[17]
[16]
bone marrow cells, and residual embryonic cells at 2p24 (rs3072), 12q24 (rs2701108), 6p21 (rs9257809),
[18]
squamo-columunar junction (SCJ). [19]
and 16q24 (rs9936833) are related to risk of BE
There are some reports suggesting an association between development. [31,32] Among these SNPs, rs9936833 at
p63 and intestinal metaplasia. p63 null embryos have 16q24 is located close to FOXF1, which is a transcription
[20]
idiopathic metaplasia in SCJ. It has been shown that factor in the SHH signaling pathway. Interestingly,
genetic alterations in metaplastic cells in mice lacking FOXF1 is associated with embryonic development
[21]
p63 were similar to those in human BE. It has also of gastrointestinal tract formation, especially the
been suggested that epithelium with such genetic changes esophagus. Also, the importance of FOXP3, at
[33]
may originally exist at SCJ. Also, lack of SRY (sex 3p14 (rs2687201), which is also known to possess a
determining region Y) box 2 (SOX2) induces columnar role in esophageal organogenesis, is based on analyzing
[34]
changes in esophageal epithelium in mice models. datasets of BE or EAC cases. 19p13 (rs10419226) and
[22]
Both p63 and SOX2 are essential for squamous epithelial 9p22 (rs11789015), with signifi cant relation to BE and
formation during organogenesis. Although these fi ndings EAC, has also been identifi ed. rs10419226 SNPs at 19p13
were based on studies using rodent esophagus, there are are known as an intronic variant of cAMP-regulated
structural differences in the esophageal between rodents transcriptional co-activators (CRTC1 ). CRTC signaling
and human. For example, in rodents, the esophagus lacks exerts oncogenic activities when activated by loss of
submucosal glands and SCJ is located in mid-stomach. LKB1 through transcriptional activation of LYPD3,
[35]
Therefore, fi ndings in rodent models may not be which contributes to esophageal tumor progression.
applicable to human BE. rs11789015 SNP at 9p22 is located at the intron region
of BARX1. BARX1 is a transcription factor involved in
Molecular and Genetic Alterations Related tracheal and foregut organogenesis in developing mouse
to Intestinal Metaplasia and Intestinal embryos. [36,37] These fi ndings suggest that key molecules
Differentiation in BE development may overlap with those in esophageal
development.
Sonic hedgehog (SHH)/bone morphogenetic protein
(BMP) signaling plays an important role in the Wnt/β-catenin, and Notch are critical signaling for
development of columnar metaplasia, being associated intestinal differentiation. Wnt family is one of the
with organogenesis, especially of the esophageal. These fundamental mechanisms of cell proliferation, polarity,
[38]
are critical molecules for separating trachea from the and differentiation. Wnt signaling pathways include
esophagus [23] and are involved in the development of Wnt/β-catenin canonical pathway and Wnt/calcium
cell-renewable epithelium. [24] Expressions of SHH and or Wnt/planar cell polarity non-canonical pathway.
BMP4 are usually low in human squamous epithelia. In Among these, Wnt/β-catenin pathway is associated with
BE tissue, however, SHH/BMP4 signaling induces SRY intestinal type gene expressions. [39,40] Wnt signaling also
(sex determining region Y) box 9 (SOX9). [25,26] SOX9 regulates CDX gene expression, which controls intestinal
[41]
subsequently induces CDX2 and MUC2 expression, differentiation, and homeostasis. Notch signaling
124 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦