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Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review)

  • Authors:
    • Uche Samuel Ndidi
    • Muhammad Awwal Abdullahi
    • Ibrahim Sofiyullahi
    • Jael Ejura Odoh
    • Bruno Raphael Ribeiro Cavalcante
    • Clarissa A. Gurgel Rocha
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Kaduna 810222, Nigeria, Department of Medicine and Surgery, College of Health Sciences, Federal University Lokoja, Lokoja, Kogi 260101, Nigeria, Pathology and Molecular Biology Laboratory, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, BA 40296‑710, Brazil
    Copyright: © Ndidi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 57
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    Published online on: May 6, 2026
       https://doi.org/10.3892/wasj.2026.472
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Abstract

Cancer is a heterogeneous group of diseases that can originate in any tissue or organ of the body, which is characterized by the uncontrollable proliferation of abnormal cells and, in some cases, the invasion of nearby tissues or other parts of the body. In recent decades, research has expanded beyond cancer cells, considering the complex interactions within the surrounding tissues due to the heterogeneous nature of cancer. Notably, cancer cells release extracellular vesicles (EVs) into the tumor microenvironment (TME), which influence stromal cells; specifically, they induce the reprogramming of fibroblasts into the cancer‑associated fibroblast (CAF) phenotype, making these cells important targets of EV‑mediated cross‑talk. Accordingly, CAFs serve a key role in tumorigenesis, angiogenesis, tumor development, metastasis and drug resistance by secreting various pro‑oncogenic factors. In addition, CAFs can secrete EVs, which further contribute to these processes. These EVs function as a unique form of intercellular communication that can promote cell proliferation and survival, help shape the TME, and increase invasive and metastatic activity. The present review was prompted by the growing recognition of the crucial yet still incompletely understood role of CAF‑derived EVs from the TME in driving tumorigenesis, growth and metastasis, highlighting the need for further exploration.
View Figures

Figure 1

Overview of the TME. (A) A tumor mass
within its surrounding microenvironment. (B) A magnified view of
the TME, highlighting the diverse cellular components and
structural elements present. These include malignant cancer cells;
stromal cells such as MSCs, fibroblasts and CAFs; immune cells
including T-lymphocytes, B-lymphocytes, macrophages, dendritic
cells and NK cells; as well as red blood cells and blood vessels.
These components form a dynamic and interactive microenvironment
that supports tumor progression and cellular cross-talk. CAF,
cancer-associated fibroblast; MSC, mesenchymal stromal cell; NK,
natural killer; TME, tumor microenvironment.

Figure 2

Biogenesis of EVs in activated
fibroblasts/CAFs. Exosomes (30-150 nm) originate from the endosomal
pathway through inward budding of the endosomal membrane, leading
to the formation of ILVs within MVBs. ILV formation occurs via
ESCRT-dependent and ESCRT-independent mechanisms, and enables
selective cargo sorting, including proteins, lipids and nucleic
acids. MVBs may fuse with lysosomes for degradation (1) or with the plasma membrane to release
ILVs as exosomes into the extracellular space (2). By contrast, microvesicles (100-1,000
nm) are generated by direct outward budding (ectocytosis) of the
plasma membrane. These EV biogenesis pathways in CAFs contribute to
intercellular communication within the tumor microenvironment. CAF,
cancer-associated fibroblast; ESCRT, endosomal sorting complexes
required for transport; EV, extracellular vesicle; ILV,
intraluminal vesicle; MVB, multivesicular body.

Figure 3

Structural and molecular composition
of EVs. EVs are enclosed by a lipid bilayer enriched in
cholesterol, sphingomyelin and phosphatidylserine, and display
transmembrane proteins and surface receptors that mediate cellular
recognition and uptake. The EV lumen contains diverse bioactive
cargo, including nucleic acids (DNA, miRNAs, siRNAs and lncRNAs),
cytoskeletal and contractile proteins, and other functional
proteins. Together, these components enable EVs to participate in
intercellular communication by regulating gene expression, signal
transduction, metabolic reprogramming and immune modulation within
the tumor microenvironment. EV, extracellular vesicle; lncRNA, long
non-coding RNA; miRNA, microRNA; siRNA, small interfering RNA.

Figure 4

Role of EVs in tumor-stromal
communication within the TME. (A) Cancer cells release EVs
containing bioactive cargo such as miRNAs, proteins and metabolites
into the TME. (B) These EVs are taken up by stromal progenitor
cells, including MSCs and pericytes, leading to their activation
and differentiation into CAFs. (C) Activated CAFs secrete their own
EVs enriched with signaling molecules that are transferred back to
cancer cells. (D) Uptake of CAF-derived EVs by cancer cells
promotes tumor-supporting processes, including therapy resistance,
angiogenesis, EMT, metastasis and immune modulation. CAF,
cancer-associated fibroblast; EMT, epithelial-mesenchymal
transition; EV, extracellular vesicle; miRNA/miR, microRNA; MSC,
mesenchymal stromal cell; TME, tumor microenvironment.
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Copy and paste a formatted citation
Spandidos Publications style
Ndidi US, Abdullahi MA, Sofiyullahi I, Odoh J, Ribeiro Cavalcante B and Gurgel Rocha CA: Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review). World Acad Sci J 8: 57, 2026.
APA
Ndidi, U.S., Abdullahi, M.A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., & Gurgel Rocha, C.A. (2026). Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review). World Academy of Sciences Journal, 8, 57. https://doi.org/10.3892/wasj.2026.472
MLA
Ndidi, U. S., Abdullahi, M. A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., Gurgel Rocha, C. A."Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review)". World Academy of Sciences Journal 8.4 (2026): 57.
Chicago
Ndidi, U. S., Abdullahi, M. A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., Gurgel Rocha, C. A."Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review)". World Academy of Sciences Journal 8, no. 4 (2026): 57. https://doi.org/10.3892/wasj.2026.472
Copy and paste a formatted citation
x
Spandidos Publications style
Ndidi US, Abdullahi MA, Sofiyullahi I, Odoh J, Ribeiro Cavalcante B and Gurgel Rocha CA: Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review). World Acad Sci J 8: 57, 2026.
APA
Ndidi, U.S., Abdullahi, M.A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., & Gurgel Rocha, C.A. (2026). Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review). World Academy of Sciences Journal, 8, 57. https://doi.org/10.3892/wasj.2026.472
MLA
Ndidi, U. S., Abdullahi, M. A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., Gurgel Rocha, C. A."Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review)". World Academy of Sciences Journal 8.4 (2026): 57.
Chicago
Ndidi, U. S., Abdullahi, M. A., Sofiyullahi, I., Odoh, J., Ribeiro Cavalcante, B., Gurgel Rocha, C. A."Cancer‑associated fibroblast‑derived extracellular vesicles in the tumor microenvironment and their medical importance (Review)". World Academy of Sciences Journal 8, no. 4 (2026): 57. https://doi.org/10.3892/wasj.2026.472
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