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
(1) de Carvalho TG (2) Lara P (3) Jorquera-Cordero C (4) Arago CFS (5) de Santana Oliveira A (6) Garcia VB (7) de Paiva Souza SV (8) Schomann T (9) Soares LAL (10) da Matta Guedes PM (11) de Arajo Jnior RF
(1) de Carvalho TG (2) Lara P (3) Jorquera-Cordero C (4) Arago CFS (5) de Santana Oliveira A (6) Garcia VB (7) de Paiva Souza SV (8) Schomann T (9) Soares LAL (10) da Matta Guedes PM (11) de Arajo Jnior RF
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-_ 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.
Author Info:
(1) Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Department of Radiology, Leiden University Medical Center, Leiden,
the Netherlands; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil. (2) Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: p.lara_arenas@lumc.nl. (3) Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands. (4) Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Medicines Quality Control Laboratory (LCQMed), Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil. (5) Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Medicines Quality Control Laboratory (LCQMed), Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil. (6) Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil. (7) Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil. (8) Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. (9) Post Graduation Program in Therapeutic Innovation, Department of Pharmaceutical Sciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil. (10) Department of Parasitology and Microbiology and Post-Graduation Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal, RN, Brazil. (11) Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil. Electronic address: fernandes.araujo@ufrn.br.
Citation: Biomed Pharmacother 2023 Oct 11 168:115663 Epub10/11/2023
