The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis

Abstract

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

“…Contradictory data have also been reported for melanoma. Loss of the AhR enhanced tumorigenicity in vivo and leflunomide inhibited melanoma cell proliferation (Contador-Troca et al 2013; O’Donnell et al 2012); however, it was also reported that AhR knockdown decreased growth (Barretina et al 2012) and TCDD increased invasion and expression of MMPs (Villano et al 2006). Differences in these data may be cell context-dependent and mouse model-specific and need further investigation.…”

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

“…Although dioxin is classified as a human carcinogen- acting through the AhR- there is controversy for the role of the AhR in cancer development. In some studies, the AhR acts as a potent tumor suppressor, recently being shown to repress melanoma growth55, liver carcinogenesis56 and inflammation-associated colorectal tumorigenesis57. Genetic variations in AHR are also implicated in lung cancer susceptibility amongst smokers, where such variation may affect AhR protein expression and/or activity585960.…”

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways

“…In some respects this is not surprising, as AhR-null mice develop increased ischaemia-induced angiogenesis compared to wt mice [61], as well as cardiac hypertrophy consequent to coronary neovascularization, concomitant with increased VEGFA and hypoxia-inducible factor 1α expression in the heart [62,63]. However, multiple studies have shown that AhR-null mice have hepatic vascular defects, impaired angiogenesis, decreased cell proliferation and migration that can compromise tumour xenograft growth [62,[64][65][66][67]. This differential effect of AhR, resulting in pro-or anti-angiogenesis, may be cell type-and tissue-dependent [64].…”