Abstract
In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). In this study, we further validated our findings on a prospective cohort of primary VSCC cases, where immunohistochemical staining confirmed that key Hh pathway components were overexpressed in VSCC compared to normal vulval epithelium. We also undertook a series of in vitro studies to determine the extent of Hh pathway activation in VSCC-derived cell lines, and examine the consequences of pathway inhibition on the growth of these cells. We found that of six cell lines tested, four displayed elevated baseline Hh pathway activity that was dependent on SHH ligand, or in one case, a PTCH1 gene mutation. Hh signalling appeared necessary to sustain cell growth, as SHH ligand depletion with Robotikinin or SMO inhibition, either with chemical inhibitors (Itraconazole or LDE-225) or SMO-specific siRNA, attenuated GLI1 activity and cell proliferation in both monolayer and organotypic raft culture. Furthermore, treatment of Hh-dependent cell lines with SMO inhibitors sensitised cells to Cisplatin. Findings from our study offer us the opportunity to explore further the development of targeted chemotherapy for women with VSCC driven by aberrant Hh activation.
Highlights
In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC)
To consolidate the findings of our previous study, IHC staining was performed on a cohort of 49 primary VSCC tumour biopsies and 15 age-matched normal vulval epithelial tissue specimens, to evaluate expression of key Hh pathway components (SHH, PTCH1, GLI1, GLI2 and GLI3); the latter obtained from patients undergoing vulva/perineal surgery unrelated to pre-malignant or malignant disease
In both tumour and normal vulval epithelium, expression of SHH ligand was localised to the cytosol; PTCH1 to the membrane, cytosol and nucleus; and GLI1, GLI2 and GLI3 to the cytosol and nucleus (Fig. 1)
Summary
We showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). Vulval cancer comprises 6% of all gynaecological malignancies reported in the UK, with squamous cell carcinoma (VSCC) contributing approximately 90% of cases. Dysregulation of Hh signalling may follow overexpression of HH ligand, loss-of-function in PTCH1, gain-offunction mutations in SMO and epigenetic modulation of pathway components[12,13,14]. As the Hh pathway usually is “switched off ” or only transiently activated in most tissues in adulthood, our findings offer the opportunity to explore the clinical efficacy of Hh inhibitors as a new targeted therapy for VSCC, either alone, or in combination with current chemotherapy regimens; especially in those with locally advanced or metastatic disease where surgery has a limited role[2]
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