Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation

Background: Hedgehog (Hh) signaling was assessed in patients with primary cervical carcinoma who were receiving chemoradiation. Because the up-regulation of Hh has been reported in response to hypoxia, the authors examined associations between Hh gene expression and measurements of HP5 (the percentage of oxygen pressure readings in each tumor <5 mm Hg) and interstitial fluid pressure (IFP).

Methods: Sonic hedgehog (SHH), Indian hedgehog (IHH), patched 1 and 2 (PTCH1 and PTCH2), smoothened (SMO), and glioma-associated oncogene family zinc finger 1 (Gli1) expression levels were determined using quantitative reverse transcriptase-polymerase chain reaction analysis on 85 frozen samples of primary cervical carcinoma and on 16 normal cervical samples. Clinicopathologic data were collected prospectively. Possible correlations between Hh expression and tumor hypoxia (HP5 and IFP) measured at the time of biopsy, the time to local recurrence, and disease-free survival (DFS) were examined.

Results: At least 1 member of the Hh pathway was elevated in all but 1 tumor compared with normal tissue (P < .0001). Hh gene expression was heterogeneous with SHH, IHH, and GLI exhibiting bimodal distribution. Elevation of SHH expression (P = .04) and low SMO expression (P = .0007) were associated with HP5. The risk of local recurrence was associated with the up-regulation of SMO (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.00-5.82; P = .044), the up-regulation of >3 Hh genes (HR, 2.56; 95% CI, 1.09-6.00; P = .026), tumor size (HR, 1.41; 95% CI, 1.14-1.74; P = .0015), and lymph node-positive disease (HR, 2.82; 95% CI, 1.16-6.86; P = .022).

Conclusions: The proportion of tumors that expressed Hh genes in cervical cancer was very high. The current data support a role for the Hh pathway in repopulation after chemoradiation and suggest that SMO may be a valid therapeutic target. The authors concluded that further investigation into this pathway after radiation and Hh inhibition are warranted.