The adipose tissue (AT) is an important endocrine organ. Upon energy imbalance, the adipose cells become dysfunctional, supporting the development of metabolic pathologies and tumours. The adipose cell is among the main actor of the tumor microenvironment, and is able to establish a crosstalk with the cancer cell resulting in a reciprocal reprogramming. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting the adrenal cortex. In the most aggressive forms, cancer cells infiltrate the visceral fat mass surrounding the adrenal, establishing a crosstalk between the tumour mass and the adipose microenvironment. Carbonic anhydrases (CAs) are a wide family of metalloenzymes with a relevant role in some pathologic conditions such as obesity and cancer. The objective of our study was to assess the distribution of the two CA isoforms, CAIII and CAIX, in AT (biotic samples of subcutaneous, SAT, and visceral, VAT, AT of obese and lean subjects) and in ACC tumor samples from a monocentric patient cohort by qRT-PCR, Western Blot and immunohistochemistry. We also evaluated their involvement in an in vitro coculture system between adipose stem cells, ASCs and adrenocortical cancer cells H295R, where coculture results in an increased aggressiveness and invasiveness, mimicking the interaction between adipose microenvironment and ACC in vivo. CAIII expression was higher in lean than in obese patients (SAT:FI = 26.9 ±€9.0, P = 0.01;VAT:FI = 5.2 ± 1.4, P = 0.01), while CAIX was mainly expressed in VAT than SAT of lean (FI = 480.5 ± 119.7, P = 0.01) and obese (FI = 361.4 ±€79.2, P = 0.000) subjects. CAIII expression in biopsies of ACCs stage I/II (n = 8) was significantly higher than in the aggressive ACC stage III/IV (n = 4)(FI = 4.0 ± 0.9, P = 0.001), while CAIX had an opposite behaviour (stage III/IV vs I/II FI = 5.7 ± 1.8, P = 0.03). CAIII and CAIX were also expressed in H295R. In vitro adipose differentiation of ASCs resulted in a significant increase of CAIII (adipo vs ASC FI = 54 ± 25, P = 0.04, n = 5) and CAIX (adipo vs ASC FI = 5 ± 1.5, P = 0.003, n = 5) expression. ASC-H295R cocultures resulted in an increased aggressiveness and invasiveness which was accompanied by a decrease in CAIII and an increase in CAIX expression in H295R cells in coculture vs monoculture, confirming the differences observed in ACC samples. In conclusion, our findings show an altered distribution of CAIII and CAIX expression in AT according to obesity condition, and in ACC, according to the tumor aggressiveness. Our data suggest a possible involvement of the two CAs in adipogenesis and tumor progression. We hypothesize an active role of CAIII and CAIX in the cross-talk between the adipose microenvironment and ACC, opening new prospective in the treatment of ACC with selective CA inhibitors.
22 May 2021 - 26 May 2021