Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response.
OBJECTIVE
Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown.


METHODS
The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation.


RESULTS
We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells.


CONCLUSIONS
These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.
Sims-Mourtada
Jennifer
J
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Izzo
Julie G
JG
Apisarnthanarax
Smith
S
Wu
Tsung-Teh
TT
Malhotra
Usha
U
Luthra
Rajyalashmi
R
Liao
Zhongxing
Z
Komaki
Ritsuko
R
van der Kogel
Albert
A
Ajani
Jaffer
J
Chao
K S Clifford
KS
D000230:Adenocarcinoma / Q000378:metabolism* / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000628:therapy*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D011836:Radiation Tolerance / Q000502:physiology*; D011878:Radiotherapy; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins