Avaliação do efeito da leptina liberada através das vesículas extracelulares derivadas de tecido adiposo de indivíduos obesos sobre o câncer de mama

A obesidade é uma doença crônica caracterizada pelo acúmulo anormal de gordura e inflamação crônica de baixo grau. Atualmente é considerada uma pandemia e, devido ao aumento da sua prevalência é um problema de saúde público, principalmente por sua associação com diversas doenças, incluindo o câncer. Evidências mostram que a obesidade está relacionada com o pior prognóstico do câncer de mama e, a leptina, é considerada importante elo entre essas duas doenças. A leptina é a principal adipocina secretada pelo tecido adiposo (TA) branco e, no contexto da obesidade, tem seus níveis aumentados, inclusive nas vesículas extracelulares (VEs) liberadas por adipócitos derivados de TA obeso. As VEs são capazes de modular o microambiente, por realizarem comunicação célula-célula, e promovem alguns dos “Hallmaks” do câncer. Nesse contexto, com o objetivo de elucidar os mecanismos de ação da leptina liberada pelas VEs de TA obeso sobre o câncer de mama, estimulamos in vitro a linhagem celular tumoral de mama invasiva MDA-MB-231 com as VEs derivadas do TA eutrófico e obeso, na presença ou ausência do antagonista do receptor de leptina. Em seguida, analisamos a proliferação, por MTT, invasão, através de insertos transwell revestido com matrigel-like, migração, por wound healing, e produção de espécies reativas de oxigênio (EROs) intracelular, com a sonda CM-H2DCFDA. Além disso, foram avaliadas a expressão de AKT e STAT3, proteínas da via de sinalização de leptina, envolvidas nos processos de progressão tumoral, por western blotting. Nossos resultados preliminares demonstram que a leptina derivada de VEs de TA de obeso aumentam a malignidade da linhagem tumoral de mama MDA-MB-231 por promover aumento da migração, invasão, produção de EROs intracelular e ativação de AKT e STAT3Obesity is a chronic disease characterized by abnormal fat accumulation and chronic low-grade inflammation. It is currently considered a pandemic, and due to its increased prevalence, it is a public health problem, mainly associated with several diseases, including cancer. Evidence shows that obesity is related to a worse prognosis of breast cancer, and leptin is an essential link between these two diseases. Leptin is the main adipokine secreted by white adipose tissue (AT). In the context of obesity, its levels are increased, including in extracellular vesicles (EVs) released by adipocytes derived from obese AT. EVs can modulate the microenvironment by performing cell-cell communication and promoting some of the “Hallmarks” of cancer. In this context, to elucidate the mechanisms that leptin released by EVs from obese AT acts on breast cancer, we stimulated, in vitro, the invasive breast tumor cell line MDA-MB-231 with EVs released from obese or control AT in the presence or absence of the leptin receptor antagonist. Then, we analyzed the proliferation by MTT invasion through the transwell coated with matrigel-like, migration by wound healing, and intracellular ROS production with the probe CM-H2DCFDA. In addition, the expression of AKT and STAT3, proteins involved in leptin signaling and tumor progression processes, was evaluated by western blotting. Our preliminary results demonstrate that leptin derived from EVs from obese TA increases the malignancy of the MDA-MB-231 breast tumor cell line by promoting increased migration, invasion, production of intracellular ROS, and activation of AKT and STAT368 f

Adipose Tissue-Derived Extracellular Vesicles and the Tumor Microenvironment: Revisiting the Hallmarks of Cancer

Extracellular vesicles (EVs) are crucial elements that sustain the communication between tumor cells and their microenvironment, and have emerged as a widespread mechanism of tumor formation and metastasis. In obesity, the adipose tissue becomes hypertrophic and hyperplastic, triggering increased production of pro-inflammatory adipokines, such as tumor necrosis factor α, interleukin 6, interleukin 1, and leptin. Furthermore, obese adipose tissue undergoes dysregulation in the cargo content of the released EVs, resulting in an increased content of pro-inflammatory proteins, fatty acids, and oncogenic microRNAs. These alterations drive obesity-associated inflammatory responses both locally and systemically. After being ignored for a long time, adipose tissues have recently received considerable attention as a major player in tumor microenvironment-linked obesity and cancer. The role of adipose tissue in the establishment and progression of cancer is reinforced by its high plasticity and inflammatory content. Such a relationship may be established by direct contact between adipocytes and cancer cells within the microenvironment or systemically, via EV-mediated cell-to-cell communication. Here, we highlight cues evidencing the influence of adipose tissue-derived EVs on the hallmarks of cancer, which are critical for tumor malignancy