gms | German Medical Science

Objective: The Aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor initially linked to exogenic carcinogenic agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). In 2011, the tryptophan (TRP) catabolite kynurenine (KYN) was identified as the first endogenous ligand activating the AHR pathway. AHR has been shown to be involved in several biochemical pathways and cellular processes such as cell cycle, cell migration, tumorigenesis, cell migration and immune function. AHR is expressed in cells of the central nervours system and dysregulation of AHR, its nuclear translocator (ARNT), its Repressor AHRR and the KYN building Enzyme TRP-2,3-dioxygenase 2 (TDO) has been linked to poor survival in patients with Glioblastoma. In this study, we aimed to evaluate a potential role of the AHR pathway in brain metastases.

Methods: Using quantitative RT-PCR, gene expression was analyzed in 19 brain-metastases of melanoma patients, 10 control tissues from peritumoral brain areas, histopathologically classified as tumorfree and 10 glioblastoma (GBM) samples. Differences in the expression of AHR, ARNT, AHRR, TDO as well as the AHR/AHRR ratio between tumor tissue and control were analyzed using the Mann-Whitney-U test. Results are depicted in mean values with standard deviation (SD) and in Arbitrary Units (AU). A Value of p<.05 was considered significant.

Results: Both, AHR and ARNT were massively overexpressed in metastatic tissues (p<.01) (6- and 4.5-fold) compared to normal brain (AHR: 3.64 ± 2.32 vs. .58 ±.50; p<0.01 and ARNT: 3.81 ± 2.25 vs. .83 ±.48, p<.01). AHRR and TDO where not significantly upregulated (.73 ±.88 vs. .41 ±.35; p=.31and .37 ±.61 vs. .14 ±.09; p=.46). However, when comparing the ratio of the transcription factor AHR and its Repressor AHRR (AHRR/AHR) in metastatic and control tissue, the imbalance between the severely upregulated AHR in tumortissue and AHRR was distinctly significant. (.55 ±1.09 vs. .18 ±1.60 p<.01) Comparing AHR expression between malignant melanoma metastasis and GBM exhibted the following values: 3.64 ± 2.32 vs. 1.27 ± 1.89; p=.055. Moreover, ARNT was significantly elevated in metastasis compared to GBM: 3.81 ± 2.25 vs. 1.7 ±.1.15, p<.01.

Conclusion: Our data reveal a significant upregulation of key components of the AHR pathway in melanoma brain metastases in comparison to peritumoral brain and partly even GBM. This could indicate a major pathophysiological role of this pathway not only in GBMs like shown before, but also in the progression of brain metastasis. While the AHR-pathway can play a dual role in tumorigenesis, i.e. it can be both tumor-suppressive or tumor-promoting, based on these findings its role in brain metastases of melanomas should be further elucidated.