{"title":"The effects of autophagy-modifying drugs chloroquine and lithium on the skin melanoma microenvironment","authors":"Iuliia Taskaeva , Anastasia Shatruk , Igor Ivanov , Nataliya Bgatova","doi":"10.1016/j.tice.2025.102753","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Skin melanoma is a highly metastatic cancer with an increasing global incidence. Despite advancements in immunotherapy, new treatment strategies based on tumor biology are essential for improving outcomes and developing novel therapies. Autophagy plays a critical role in melanoma cell metabolism and affects the tumor microenvironment (TME). This study aims to evaluate the impact of autophagy-modifying drugs on extracellular matrix (ECM) remodeling and changes in the TME cytokine profile.</div></div><div><h3>Methods</h3><div>Immunohistochemical analysis was performed using paraffin-embedded tumor samples of B16-bearing C57BL/6 mice to assess the effects of autophagy-modifying drugs, lithium or chloroquine, on the matrix degradation proteins, their main substrates, lysyl oxidase and collagen fibril formation-associated proteins. The cytokine profile of the tumor was defined to estimate the effect of autophagy-modifying drugs on the TME.</div></div><div><h3>Results</h3><div>Chloroquine and lithium administration caused a decrease in the expression of matrix metalloproteinases, and chloroquine contributed to the accumulation of collagen type I. Moreover, chloroquine dramatically decreased LOX levels. Decorin expression levels were reduced in tumors of mice treated with chloroquine or lithium. Significant changes in the cytokine profile were detected after chloroquine treatment, with increased expression of IL1, IL4, IL6, M-CSF, TGFβ2 and TNF-α genes observed in the tumors.</div></div><div><h3>Conclusion</h3><div>Autophagy-modifying drugs affect the TME, in particular, chloroquine promotes ECM remodeling, accumulation of collagen type I deposits and probably the formation of abnormal collagen fibril structures. In addition, chloroquine-treated mice showed high expression of pro-tumorigenic cytokines and growth factors, such as IL1, IL4, IL6, M-CSF, TGFβ2 and TNF-α in the TME.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"93 ","pages":"Article 102753"},"PeriodicalIF":2.5000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tissue & cell","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040816625000333","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ANATOMY & MORPHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Skin melanoma is a highly metastatic cancer with an increasing global incidence. Despite advancements in immunotherapy, new treatment strategies based on tumor biology are essential for improving outcomes and developing novel therapies. Autophagy plays a critical role in melanoma cell metabolism and affects the tumor microenvironment (TME). This study aims to evaluate the impact of autophagy-modifying drugs on extracellular matrix (ECM) remodeling and changes in the TME cytokine profile.
Methods
Immunohistochemical analysis was performed using paraffin-embedded tumor samples of B16-bearing C57BL/6 mice to assess the effects of autophagy-modifying drugs, lithium or chloroquine, on the matrix degradation proteins, their main substrates, lysyl oxidase and collagen fibril formation-associated proteins. The cytokine profile of the tumor was defined to estimate the effect of autophagy-modifying drugs on the TME.
Results
Chloroquine and lithium administration caused a decrease in the expression of matrix metalloproteinases, and chloroquine contributed to the accumulation of collagen type I. Moreover, chloroquine dramatically decreased LOX levels. Decorin expression levels were reduced in tumors of mice treated with chloroquine or lithium. Significant changes in the cytokine profile were detected after chloroquine treatment, with increased expression of IL1, IL4, IL6, M-CSF, TGFβ2 and TNF-α genes observed in the tumors.
Conclusion
Autophagy-modifying drugs affect the TME, in particular, chloroquine promotes ECM remodeling, accumulation of collagen type I deposits and probably the formation of abnormal collagen fibril structures. In addition, chloroquine-treated mice showed high expression of pro-tumorigenic cytokines and growth factors, such as IL1, IL4, IL6, M-CSF, TGFβ2 and TNF-α in the TME.
期刊介绍：
Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed.
Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.
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