Hedgehog: an Attribute to Tumor Regrowth after Chemoradiotherapy and a Target to Improve Radiation Response

Abstract

Purpose: 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. Experimental Design: 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 G 1 -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.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Based on cancer stem cell theory, one would anticipate that Hh-signaling activation may exert chemotherapy or radiotherapy resistance in cancer if this pathway has a major role in cancer stem cell functions (Reya et al, 2001). Several studies have shown that Hh-signaling activation is associated with chemotherapy resistance or radiotherapy resistance (Sims-Mourtada et al, 2006;Yoshikawa et al, 2008;Olive et al, 2009), supporting that hedgehog signaling activation has a role in cancer stem cell functions. It was recently reported that Hh-signaling inhibitor enhances the delivery of chemotherapy in a mouse model of pancreatic cancer (Olive et al, 2009).…”

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

“…Recent studies suggest that SHH signaling activation upregulates the expression of ABCG2 in several cancers. 12,13 Although inappropriate activation of the SHH signaling pathway has been shown in many cancers, SHH proteins have not been assessed in diffuse large B-cell lymphoma, nor have ABCG2 protein levels been assessed in these tumors. Here, we investigated expression of SHH signaling proteins and ABCG2 in diffuse large B-cell lymphoma.…”

Radioresistance and Cancer Stem Cells: Survival of the Fittest

“…The Hh pathway is thought to play an important role in regulating CSC proliferation, survival and maintenance [58][59][60][61][62]. Hh was first discovered in Drosophila and it is a highly conserved pathway across multiple organisms.…”

“…All of these reveal the essential role of Hh signaling pathway in controlling the behavior of CSCs and offer new therapeutic possibilities. Although the specific role Hh signaling has in radiation resistance remains an area of active investigation, it is reported that activation of Hh signaling pathway may promote the repopulation of CSCs after radiotherapy, thereby, contributing to both radiation resistance and treatment failure [61]. To determine the role of Hh signaling in therapeutic resistance to radiotherapy, Sims-Mourtada et al analyzed esophageal tumor samples from 43 radiotherapy resistant cancer patients and showed that 83.7% had activated Hh signaling defined by Hh expression and nuclear GLI localization [61].…”