gms | German Medical Science

Objective: The dioxin/aryl hydrocarbon receptor (AhR) is a transcription factor, to which a role in human cancerogenesis, cell cycle progression and transforming growth factor-β (TGF-β) has been attributed. The endogenous tumor-promoting ligand of the human AhR kynurenine was discovered recently. It is constitutively generated by tumor cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived tryptophan-degrading enzyme. The TDO-AhR pathway is active in human brain tumours and is associated with poor survival.

Method: We used real-time RT-PCR to quantify the expression of AhR, TDO, the AhR nuclear translocator (ARNT), and the repressor of AhR (AHRR). The latter is a putative tumor suppressor gene in multiple human cancers. SDHA served as a housekeeping gene. We examined a set of 70 human glioma samples representing the differences between the three degrees of malignancy (WHO grade II-IV), primary and recurrent gliomas, pure and mixed astrocytic tumors, with and without radio- and/or chemotherapy. We also studied whether the expression profile changes as the same tumor progresses in 20 individual patients. Results are reported as ΔCt between the marker and reference gene mRNA levels.

Results: Both the expression of AhR and ARNT were significantly increased after chemotherapy (CTx). The AhR was upregulated from 0.69 before CTx to 3.49 after CTx in secondary GBM and from 0.76 to 1.51 in primary GBM respectively (p=0.003). The mRNA expression of ARNT was increased from 1.37 before CTx to 2.7 after CTx in secondary- and from 0.86 to 1.68 in primary GBM (p=0.009). In contrast, TDO expression was downregulated during temozolomide CTx. In secondary GBM it was increased from 0.46 to 0.17 and in primary GBM from 0.77 to 0.35 (p=0.03). Moreover, ARNT was significantly upregulated in grade II and grade III astrocytomas compared to peritumoral tissue (p<0.0001). TDO expression was significantly higher in GBMs compared to lower grade astrocytomas (p=0.001). Diffuse astrocytomas displayed significantly lower levels of AHRR compared to high grade gliomas. The other groups, such as pure and mixed astrocytic tumors did not differ.

Conclusions: AhR and ARNT were significantly upregulated after chemotherapy in glioblastoma. In contrast, TDO was significantly downregulated. These results provide evidence for an important pathophysiological role of the AhR with profound implications for cancer and immune biology. Furthermore, these results could have broad implications for potential targeted therapies.