La Civita, Evelina (2025) Adipocyte-Released FABP4 Enhances Renal Cancer Cell Motility. [Tesi di dottorato]

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Abstract

Adipose tissue is a highly active endocrine organ capable of regulating energy balance, food intake, inflammation, and metabolism by releasing soluble factors known as adipokines. Obesity is a well-established risk factor for the development of several cancers, including clear cell renal cell carcinoma (ccRCC). CcRCC is the most lethal among all renal cancer subtypes and is strongly associated with a high body mass index and an increased thickness of perirenal adipose tissue (PRAT), the visceral fat depot surrounding the renal capsule. In this context, PRAT adipocytes may influence ccRCC progression through the release of paracrine-acting adipokines enhancing tumor cell viability and migration. In this thesis, I focused on the role of Fatty Acid Binding Protein 4 (FABP4), one of the factors secreted by adipocytes, known to affect the malignant phenotype of several tumors, including colon, prostate, and breast cancer. To clarify the role of FABP4 released by PRAT in modulating ccRCC tumor cell motility in vitro, I collected conditioned media from mature adipocytes (Ad-CM) isolated from PRAT samples obtained from ccRCC patients and healthy donors. Through this approach, I demonstrated that Ad-CM derived from tumor patients contains higher concentration of FABP4 compared to that obtained from Healthy Donors (HD). To determine the role of adipocyte-derived FABP4 in ccRCC tumor progression, I evaluated proliferation and migration in the ccRCC cell lines 786-O and ACHN, treating ccRCC cells with Ad-CM from cancer patients, Ad-CM from HD, and recombinant FABP4, alone or in combination with BMS309403, a selective FABP4 inhibitor. I demonstrated that treatment with Ad-CM from both tumor patients and HD increases proliferation in ACHN cells in a FABP4-independent manner. Subsequently, I assessed the effect of Ad-CM on cell motility, showing that Ad-CM derived from tumor patients induces a significant increase in cell migration in both 786-O and ACHN cells, and that this effect is partially inhibited by BMS309403 treatment. Moreover, treatment of both cell lines with recombinant FABP4 induces an increase in cell motility comparable to that observed with Ad-CM from tumor patients. Overall, these findings demonstrate that conditioned media from peritumoral adipocytes promote cell migration through a mechanism involving FABP4. Hence, this adipokine represents a common link between obesity and cancer, suggesting its potential role as a circulating biomarker and therapeutic target for ccRCC.

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