Cell Guidance Systems, 12 August , 2024
Exosomes are small extracellular vesicles (30-150 nm) that play a crucial role in cell-to-cell communication by transferring proteins, lipids, and nucleic acids between cells. Macrophage-derived exosomes (MDEs) have garnered significant attention in recent years for their role in tumorigenesis, the process by which normal cells transform into cancer cells. Macrophage-Derived Exosomes have key roles in tumorigenesis
Promotion of Tumor Growth and Survival
Macrophages are a major component of the tumor microenvironment (TME). These cells can be polarized into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. M2 macrophages, in particular, are known to support tumor growth and metastasis. Exosomes derived from M2 macrophages carry bioactive molecules, such as cytokines, chemokines, and growth factors, which can promote tumor cell proliferation and survival. It has been shown, for example, that MDEs can transfer miRNAs like miR-21 and miR-155, which are known to inhibit tumor suppressorgenes and promote oncogenic pathways. These miRNAs can modulate the expression of genes involved in cell cycle regulation, apoptosis, and immune evasion, thereby facilitating tumor growth and survival
Induction of Angiogenesis
Angiogenesis, the formation of new blood vessels, is a critical process in tumor development as it provides the necessary nutrients and oxygen for rapidly growing tumor cells. MDEs have been shown to carry pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). These factors carried by exosomes can stimulate endothelial cell proliferation and migration, leading to the formation of new blood vessels within the tumor. Additionally, MDEs can transfer miRNAs like miR-130a and miR-150, which further enhance angiogenesis by targeting anti-angiogenic genes.
Modulation of the Immune Response
The immune system plays a dual role in cancer, capable of both suppressing and promoting tumor growth. MDEs can modulate the immune response in favor of tumor progression. For example, MDEs can carry immunosuppressive molecules such as transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), which can inhibit the activity of cytotoxic T cells and natural killer (NK) cells, thereby allowing tumor cells to evade immune surveillance. Additionally, MDEs can promote the differentiation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which contribute to an immunosuppressive TME that supports tumor growth.
Facilitation of Metastasis
Metastasis, the spread of cancer cells from the primary tumor to distant organs, is a major cause of cancer-related mortality. MDEs can facilitate metastasis by preparing the pre-metastatic niche. They can transfer proteins and RNAs that remodel the extracellular matrix (ECM) and promote the adhesion and invasion of tumor cells. For instance, MDEs can carry integrins and MMPs that degrade the ECM, making it easier for tumor cells to invade surrounding tissues and enter the bloodstream Moreover, MDEs can transfer miRNAs that downregulate the expression of adhesion molecules on endothelial cells, thereby facilitating the extravasation of circulating tumor cells into distant tissues. This process is critical for the establishment of secondary tumors in organs such as the lungs, liver, and brain.
Alteration of Tumor Metabolism
Tumor cells often exhibit altered metabolism to support their rapid growth and survival. MDEs can influence tumor metabolism by transferring metabolic enzymes and regulatory RNAs. For example, MDEs can carry enzymes involved in glycolysis, such as hexokinase and pyruvate kinase, which can enhance the glycolytic activity of tumor cells/ Additionally, MDEs can transfer miRNAs that regulate metabolic pathways, thereby promoting the metabolic reprogramming of tumor cells to favor anabolic processes and energy production.
Therapeutic Implications
Given their significant role in tumorigenesis, MDEs represent a potential target for cancer therapy. Strategies to inhibit the production, release, or uptake of MDEs could disrupt the communication between macrophages and tumor cells, thereby hindering tumor progression. For instance, blocking the secretion of exosomes using inhibitors of neutral sphingomyelinase (nSMase or Rab27a, which are involved in exosome biogenesis and release, could reduce the pro-tumorigenic effects of MDEs Additionally, targeting specific molecules within MDEs, such as miRNAs or proteins, using antisense oligonucleotides or small molecule inhibitors, could mitigate their tumor-promoting activities.
Another promising approach is the use of engineered exosomes as therapeutic delivery vehicles. By loading exosomes with anti-cancer drugs, siRNAs, or miRNAs that target oncogenic pathways, it is possible to selectively deliver these therapeutic agents to tumor cells, thereby enhancing their efficacy and reducing off-target effects. Moreover, modifying the surface of exosomes to enhance their targeting to tumor cells or the TME could further improve their therapeutic potential.
Source: Cell Guidance Systems
Link: https://www.cellgs.com/blog/the-role-of-macrophage-derived-exosomes-in-cancer.html
