Dysfunctional transforming growth factor-β signaling with constitutively active notch signaling in Barrett's esophageal adenocarcinoma

Authors


I read with interest the article by Mendelson and colleagues,1 revealing aberrant transforming growth factor-β (TGF-β) and Notch signaling pathways in Barrett's esophageal adenocarcinoma. The authors stated that aberrant activation of Notch signaling could be due to the dysfunction of TGF-β signaling.1 However, I suppose that the relation of cause and effect is not certain, and that the conclusion may be overstated, because reciprocal relationship between TGF-β and Notch signaling may exist; the dysfunction of TGF-β signaling might result from activated Notch signaling (in my previous report and others),2-4 except for cases of loss of heterozygosity of Smad4.5 To confirm the relationship, functional knockdown experiments (eg, using γ-secretase inhibitor [GSI]) will be required in Figure 4B.1 One can see whether the expressions of TGF-β-mediated factors (p21, p15, p16) would revert after treatment with GSI. Some of percentages listed in Table 1 may be miscalculated.

Furthermore, my concern is that the intensity of the bands with Notch1 intracellular domain (ICN1) in Figure 2B is relatively weak (using an undesignated antibody), and that the activation of Notch signaling should be determined as specific, both in Figure 2B and 2C. Comparison with GSI-treated cells (in a knockdown state) will demonstrate clear-cut and specific activation of Notch signaling above baseline (Fig. 2C), and will show correlation between Figure 2B and 2C.

My another interest is whether BE3 cells in Figure 5B were increasing in absolute number during GSI treatment (for 72 hours). If BE3 cells undergo cell cycle arrest or apoptosis and are decreasing in number (up to ∼7 days), Notch signaling might be a potent therapeutic target in esophageal adenocarcinoma, as the authors mentioned.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The author made no disclosures.

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