Bone morphogenetic protein expression patterns in human esophageal atresia with tracheoesophageal fistula

Abstract

The organogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) remains unknown. The fistula tract appears to develop from a non-branching trifurcation of the embryonic lung bud. The non-branching growth of the fistula differs from the other lung buds and suggests a deficiency in bone morphogenetic protein (BMP) signaling, since BMPs are critical to proper lung development and branching. With IRB approval, portions of newborn human proximal esophageal pouch and distal fistula samples were recovered at the time of surgical repair of EA/TEF. The tissues were processed for immunohistochemistry. Commercially available fetal tissues were used as controls. In control tissues, BMP ligands (BMP 2, 4, and 7) were all present in the esophagus but absent in the trachea. BMPRIA was absent in both tissues. BMPRIB was detected in trachea but not in esophagus and BMPRII was detected in esophagus but not in trachea. In the EA/TEF specimens, all BMP ligands were present in the proximal esophageal pouch but absent in the fistula tract. BMPRIA and BMPRIB were not detected in either tissue. However, BMPRII was found in both fistula tract and proximal pouch. The submucosa of the fistula appears to maintain a mixed (identical neither to lung, esophagus, or trachea) BMP signaling pattern, providing one mechanism which could potentially explain the esophageal dismotility and lack of lung branching seen in the fistula/distal esophagus.

Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

“…Based on the theory that TEF originates from the tracheal bifurcation and grows down towards the stomach in a non-branching way, Crowley et al studied the expression pattern of BMP2, 4 and 7 and BMPR-IA, -IB and -II in normal human lung, trachea and esophagus samples, as well as in samples of the proximal esophageal pouch and the TEF of nine patients with EA/TEF [75]. BMP-expression patterns in the proximal pouch were the same as in normal esophagus.…”

“…Up to now, there are only few molecular studies involving human TEF material, which often included small numbers of patients [73][74][75], and the results are contradictory. Histological studies of TEF and distal esophagus show a mixed contribution of different cell types.…”

“…Using an unbiased approach, complemented with immunohistochemistry and RT-PCR, the expression of specific proteins and genes in the TEF has been studied in both animals and humans. These include NK2 Homeobox 1 (NKX2-1), Sonic HedgeHog (SHH) and members of the Bone Morphogenic protein (BMP) pathway [73][74][75][78][79][80]. Most of these experiments seem to support a respiratory origin of the TEF in humans, but the number of human TEFs examined was small, ranging from one to nine.…”

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“…The BMPR2 receptor has protein expression throughout the tissues, including TEF. Thus in general, our findings are in line with these previous studies [75].…”

Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression

“…(7) BMP signaling plays an important role in the normal development of the esophagus; dysregulation of BMP and their native antagonists can result in improper development of the esophagus in the embryonic stage. (8)(9)(10) Altered expression of BMP also results in an inflammatory response in the esophagus, (11,12) as well as onset of Barrett's esophagus, a premalignant lesion of esophageal adenocarcinoma. (13) The significance of BMP6 in esophageal SCC was revealed when a high level of BMP6 expression was correlated with shorter survival.…”