Abstract
BackgroundBasal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways.ObjectivesTo determine whether HIF1/mTOR signalling is involved in BCC and TE.MethodsWe used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45) and TE (n = 35) samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, <30%, 30–80% and >80%).ResultsAmong 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3), 73% and 75% (CAIX), 79% and 86% (GLUT1), 50% and 19% (HIF1α), 89% and 88% (pAKT), 55% and 61% (pS6), 15% and 25% (pMTOR), 44% and 63% (PHD2) and 44% and 49% (VEGF-A). CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included.ConclusionsHIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.
Highlights
Basal cell carcinoma (BCC) is the most common cancer in Caucasians
carbonic anhydrase IX (CAIX), Glut1 and prolyl hydroxylase 2 (PHD2) expression levels were significantly higher in TE when only samples with at least 80% expression were included
[12] In hypoxic conditions, hypoxia-inducible factor 1alpha (HIF1a) regulates the expression of important proteins including vascular endothelial growth factor (VEGF-A), glucose transporter 1 (GLUT1), catalytic enzymes such as carbonic anhydrase IX (CAIX) and pro-apoptotic BCL-2/ adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)
Summary
Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Its incidence is increasing by 3–10% annually, leading to a lifetime BCC risk in Caucasians of approximately 1 in 5–6. [1] Sun-exposed body sites like the head and neck are most commonly affected. [1] Histologically, BCC can be classified into three main subtypes: superficial, nodular and infiltrative. [2] Youssef et al were the first to show that BCC are epithelial tumours originating from progenitor cells of the interfollicular epidermis (IFE) and the upper infundibulum. [3] Later evidence shows that BCC can arise from the hair follicle (HF) bulge. [4] Trichoepithelioma (TE) is a similar, though benign epithelial tumour which expresses markers that are present in the outer root sheath of the HF [5,6], which suggests that TE originate from the HF as well. [6] Some TE can mimic BCC macroscopically, [6] making it difficult to differentiate between both tumours and PLOS ONE | www.plosone.org mTOR and Hypoxia Signalling in BCC and Trichoepithelioma this dilemma can extend to the microscopic level. Both BCC and TE are characterised by dermal nests of basaloid cells. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC HFs are hypoxic microenvironments, we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways
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