Immunotherapy Using Oxygenated Water and Tumor-Derived Exosomes Potentiates Antitumor Immune Response and Attenuates Malignancy Tendency in Mice Model of Breast Cancer.

Nafiseh Pakravan,Ardeshir Abbasi,Zuhair Mohammad Hassan,Alin Ciobica

doi:10.1155/2021/5529484

Nafiseh Pakravan, Ardeshir Abbasi + Show 2 more

Open Access

https://doi.org/10.1155/2021/5529484

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Abstract

Breast cancer is one of the most common type of tumor and the leading cause of death in the world's female population. Various therapeutic approaches have been used to treat tumors but have not led to complete recovery and have even damaged normal cells in the body. Moreover, metastatic tumors such as breast cancer are much more resistant to treatment, and current treatments have not been very successful in treating them and remain a challenge. Therefore, new approaches should be applied to overcome this problem. Given the importance of hypoxia in tumor survival, we aimed to test the antitumor effects of oxygenated water to decrease hypoxia along with tumor-derived exosomes to target tumor. The purpose of administering oxygenated water and tumor exosomes was to reduce hypoxia and establish an effective immune response against tumor antigens, respectively. For this purpose, the breast cancer mice model was induced using the 4T1 cell line in Balb/c mice and treated with oxygenated water via an intratumoral (IT) and/or intraperitoneal (IP) route and/or exosome (TEX). Oxygenation via the IT+IP route was more efficient than oxygenation via the IT or IP route. The efficiency of oxygenation via the two routes along with TEX led to the best therapeutic outcome. Antitumor immune responses directed by TEX became optimized when systemic (IP) and local (IT) oxygenation was applied compared to administration of TEX alone. Results demonstrated a significant reduction in tumor size and the highest levels of IFN-γ and IL-17 and the lowest levels of IL-4 FoxP3, HIF-1α, VEGF, MMP-2, and MMP-9 in the IT+IP+TEX-treated group. Oxygenated water on the one hand could reduce tumor size, hypoxia, angiogenesis, and metastasis in the tumor microenvironment and on the other hand increases the effective immune response against the tumor systemically. This therapeutic approach is proposed as a new strategy for devising vaccines in a personalized approach.

Highlights

Hypoxia is an important feature of solid tumors
The selection pressure when subjected to hypoxia leads to the survival of more malignant subpopulations of tumor cells expressing MMP-2, MMP-9, and VEGF [7,8,9]
The exosomes derived from supernatants of the 4T1 cell culture were evaluated by dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and Western blotting

Summary

Introduction

Several mechanisms are presumed to be involved in the development of hypoxic conditions within the tumor foci. They include limited perfusion and/or delivery of O2. Tumor cells adapt to hypoxia, persist in harsh conditions, and become more invasive and metastatic [1,2,3,4]. Hypoxic conditions within the tumor microenvironment lead to increased angiogenesis and subsequent resistance to treatment with a number of anticancer agents [10]. Normalization of vasculature but not antiangiogenic therapy has been proposed. This would help in restoring tissue architecture and establishing a normal level of oxygen in the damaged tissue [13]

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