The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model

Abstract

Metabolic interplay between the tumor microenvironment and cancer cells is 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 possible crosstalk with the adipose cells. Here, by using an in vitro co-culture system, we show that the interaction between adipose-derived stem cells (ASCs) and the adrenocortical cancer cell line H295R leads to metabolic and functional reprogramming of both cell types: cancer cells limit differentiation and increase proliferation of ASCs, which in turn support tumor growth and invasion. This effect associates with a shift from the paracrine cancer-promoting IGF2 axis towards an ASC-associated leptin axis, along with a shift in the SDF-1 axis towards CXCR7 expression in H295R cells. In conclusion, our findings suggest that adipose precursors, as pivotal components of the ACC microenvironment, promote cancer cell reprogramming and invasion, opening new perspectives for the development of more effective therapeutic approaches.

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

“…The effect has been mainly described in stromal fibroblast cells, however given that ASCs and CAA are fibroblast like cells, it is likely they are also important contributors. Indeed it has been reported that the “reverse Warburg effect” was induced during the co-culture of adrenocortical carcinoma cells with ASCs [ 132 ]. Ketone bodies are another catabolite produced and released by glycolytic adipocytes and they are an ideal substrate for ATP production by driving oxidative mitochondrial metabolism leading to enhanced tumor invasiveness [ 91 , 133 ].…”

Exosomal miRNAs in tumor microenvironment

“…Reshaping TME provides a niche for interaction between tumor cells and surrounding fibroblasts, endothelial cells, and immune cells [4,[6][7][8][9]. These cells interact with tumor cells through TME to induce a variety of biological events, such as appreciation, migration, angiogenesis, immunosuppression, and drug resistance for tumor development [10][11][12][13][14].…”

Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

“…The chemokine and molecular profile of the cocultures was investigated further, and it was demonstrated that the cocultures showed increased levels of CXC12 and CXC7-chemokines consistently associated with increased tumor migration. In addition, increased levels of leptin and IL-8 seemed to be implicated in the more invasive phenotype of the cancer cells in the coculture, compared to the control [ 39 ]. Indeed, several studies in the past have associated leptin with tumor aggressiveness in other solid tumors.…”