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Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea - 11/11/23

Doi : 10.1016/j.biopha.2023.115663 
Thaís Gomes de Carvalho a, d, e, Pablo Lara d, , Carla Jorquera-Cordero b, Cícero Flávio Soares Aragão c, f, Artur de Santana Oliveira c, f, Vinicius Barreto Garcia e, Shirley Vitória de Paiva Souza a, e, Timo Schomann d, Luiz Alberto Lira Soares h, Paulo Marcos da Matta Guedes g, Raimundo Fernandes de Araújo Júnior a, d, e,
a Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil 
b Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands 
c Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil 
d Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands 
e Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil 
f Medicines Quality Control Laboratory (LCQMed), Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil 
g Department of Parasitology and Microbiology and Post-Graduation Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal, RN, Brazil 
h Post Graduation Program in Therapeutic Innovation, Department of Pharmaceutical Sciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil 

Corresponding author at: Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.Department of Radiology, Leiden University Medical CenterLeidenthe Netherlands⁎⁎Correspondence to: University Campus, Federal University of Rio Grande do Norte, Morphology Department, Brazil.University Campus, Federal University of Rio Grande do Norte, Morphology DepartmentBrazil.

Abstract

Colorectal cancer is still unmanageable despite advances in target therapy. However, extracellular vesicles (EVs) have shown potential in nanomedicine as drug delivery systems, especially for modulating the immune cells in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), alone or in combination (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines and prevent metastasis in mice of allograft and peritoneal colorectal cancer models. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or particularly M1EV4 downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastasis in the peritoneum, liver, and lungs. STAT3, NF-kB, and AKT were the major genes downregulated by of M1EV systems. Tumor-associated macrophages (TAMs) shifted from an M2 phenotype (CD163) to an M1 phenotype (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR1, survivin, vimentin, and PD-L1 after treatment with systems of M1EVs. The study shows that EVs from M1 antitumor macrophages can transport drugs and enhance their immunomodulatory and antitumor activity by modulating pathways associated with cell proliferation, migration, survival, and drug resistance.

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Graphical Abstract




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Highlights

M1EV systems modulated the tumor progression in TME of CCR primary tumors.
M1EV4s reduced metastatic niches in the peritoneum, liver, and lungs.
M1EV systems improved immune response by upregulating CD8 lymphocytes in TME.
Increased antitumoral response by blocking M2TAM-stimulated STAT3/NF-κB/AKT signals.

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Keywords : EVs, Macrophages 1, STAT3, AKT, NF-κB, Metastasis, Colorectal cancer


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Vol 168

Article 115663- décembre 2023 Retour au numéro
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