Endocrine Abstracts

The metabolic interplay occurring between the tumor microenvironment and cancer cells may represent a potential target for novel anti-cancer approaches. Among stromal components, adipocytes and adipose precursors have been shown to actively participate in tumor progression in several solid malignancies. In adrenocortical carcinoma (ACC), a rare endocrine neoplasia with a poor prognosis, cancer cells often infiltrate the fat mass surrounding the adrenal organ, enabling a possible crosstalk with the adipose cells. The molecular biology underlying adrenocortical carcinoma (ACC) development and growth remains to be fully elucidated.

We set up an in vitro co-culturing system to study the effects of human white adipose stem cells (ASCs) on the ACC H295R cell line, in order to investigate the role of the adipose microenvironment on ACC evolution. Cell proliferation rate significantly increased in both ASCs (2.6-fold, P < 0.001) and H295R cells (1.4-fold, P < 0.005) after 9 day co-culture compared to the mono-culture condition, with a parallel increase in glucose uptake (2.1-fold, P < 0.001 and 1.2-fold, P < 0.001, for ASCs and H295R respectively).

When co-cultured with ASCs, H295R cells showed a significant increased cell migration rate (1.8-fold, P < 0.05 at 48 hours) and expression of migration-related protein (i.e. FAK, RhoA and Fascin-1), as well as a higher invasion ability (1.6-fold, P < 0.001). A reciprocal influence of the two cell types was further demonstrated by assessing H295R cells ability to influence ASC differentiation, resulting in a significant decrease in the expression of stem genes, such as Bmi1, Nanog and Oct-4 (2.8, 3.1 and 1.3-fold, respectively) and an increased expression of the myofibroblast-like marker α-SMA. Furthermore, in vitro-induced differentiation of ASCs in the presence of H295R cells resulted in an impaired adipocyte maturation, as indicated by the significant decrease observed both in the expression of specific markers, such as Adiponectin, FABP4 and HSL (0.28, 0.25 and 0.27-fold, respectively) and intracellular lipid content (0.58-fold, P < 0.001).

In conclusion, our results support the occurrence of a specific crosstalk between ACC and its adipose microenvironment, leading to cancer cell reprogramming associated with increased invasiveness, opening new perspectives for the development of more effective therapeutic approaches.

Funds: Associazione Italiana Ricerca sul Cancro (AIRC) Investigator Grant to M. L. (grant # IG2015-17691).

Keywords: adipose precursors, adipogenesis, invasion, cancer, cell reprogramming.