Dami Aiyejuto

Background: Lung cancer accounts for roughly 19.4% of all cancer-related deaths worldwide, and non–small cell lung cancer (NSCLC) represents the majority of diagnosed cases.¹ Patients with metastatic disease face a poor prognosis, with a five-year survival rate near 8%.² Tumor growth depends on angiogenesis, which produces structurally abnormal, permeable vessels that facilitate tumor cell dissemination.^2,3 This process is sustained by continuous communication between tumor cells and the surrounding microenvironment, mediated in part by exosomes—nano-sized extracellular vesicles that transfer functional cargo, including microRNAs (miRNAs), from cancer cells to recipient endothelial cells.^3,4 In NSCLC, exosomal miRNAs reprogram human umbilical vein endothelial cells (HUVECs) to promote angiogenesis, a hallmark of tumor progression.^4,5 Although exosome-mediated pro-angiogenic signaling has been established, the specific miRNAs responsible, their endothelial targets, and whether multiple miRNAs converge on distinct anti-angiogenic regulators remain incompletely understood.^4–8

Objective: In this narrative review, we examined how tumor-derived exosomal miRNAs drive angiogenesis in NSCLC by silencing distinct anti-angiogenic regulators in endothelial cells.

Search Methods: An online search of the PubMed database was conducted for literature published between 2017 and 2026 using the keywords “non–small cell lung cancer,” “exosomes,” “microRNA,” “angiogenesis,” and “endothelial cells.”

Results: Five primary studies each identified a distinct tumor-derived exosomal miRNA that silences a different anti-angiogenic gatekeeper in endothelial cells. Exosomal miR-141 was enriched in NSCLC patient exosomes and directly suppressed the growth arrest-specific homeobox gene (GAX), promoting HUVEC proliferation, migration, and tube formation.⁴ Exosomal miR-619-5p, the most potent pro-angiogenic miRNA in a multi-cell-line screen, targeted the calcineurin inhibitor RCAN1.4; its exosomal loading was enhanced under hypoxia, and plasma levels were elevated in patients.⁶ Exosomal miR-1260b suppressed homeodomain-interacting protein kinase-2 (HIPK2), a tumor suppressor that destabilizes HIF-1α and inhibits VEGF signaling, and elevated plasma levels correlated with advanced stage, metastasis, and worse overall survival.⁷ Exosomal miR-3157-3p, elevated in metastatic patients, simultaneously suppressed TIMP2 and KLF2, upregulating VEGF, MMP2, and MMP9 while disrupting tight junction proteins to increase vascular permeability.⁸ Exosomal miR-197-3p suppressed both TIMP2 and TIMP3 in lung adenocarcinoma, activating VEGFR2/ERK signaling and MMP-mediated matrix remodeling.⁹ Across these studies, dual-luciferase reporter assays confirmed direct target binding, and xenograft and chorioallantoic membrane models confirmed increased microvessel density in vivo.^4,6–9

Conclusion: Collectively, these findings demonstrate that NSCLC cells do not rely on a single exosomal miRNA but deploy parallel pro-angiogenic signals through distinct endothelial regulators, suggesting that blocking a single miRNA–target axis may be insufficient.^4,6–9 Convergence on shared effectors, particularly TIMP2 and the VEGF/HIF-1α axis, identifies potential nodes for combination therapeutic strategies, and elevated circulating exosomal miR-619-5p and miR-1260b support the development of exosomal miRNA panels as non-invasive biomarkers.^6,7 Despite this strong preclinical evidence, clinical translation remains limited by the absence of standardized exosomal miRNA detection methods and by delivery challenges related to specificity and off-target effects. Future studies should determine whether combined inhibition of multiple exosomal miRNAs or their shared endothelial targets can effectively disrupt this parallel signaling network and improve anti-angiogenic therapeutic outcomes in NSCLC.^4,6–9

Works Cited

1. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-454. doi:10.1038/nature25183
2. Jiang C, Zhang N, Hu X, Wang H. Tumor-associated exosomes promote lung cancer metastasis through multiple mechanisms. Mol Cancer. 2021;20(1):117. doi:10.1186/s12943-021-01411-w
3. Duma N, Santana-Davila R, Molina JR. Non–small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019;94(8):1623-1640. doi:10.1016/j.mayocp.2019.01.013
4. Wang W, Hong G, Wang S, Gao W, Wang P. Tumor-derived exosomal miRNA-141 promote angiogenesis and malignant progression of lung cancer by targeting growth arrest-specific homeobox gene (GAX). Bioengineered. 2021;12(1):821-831. doi:10.1080/21655979.2021.1886771
5. Martinez-Espinosa I, Serrato JA, Ortiz-Quintero B. The role of exosome-derived microRNA on lung cancer metastasis progression. Biomolecules. 2023;13(11):1574. doi:10.3390/biom13111574
6. Kim DH, Park S, Kim H, et al. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer Lett. 2020;475:2-13. doi:10.1016/j.canlet.2020.01.023
7. Kim DH, Park H, Choi YJ, et al. Exosomal miR-1260b derived from non-small cell lung cancer promotes tumor metastasis through the inhibition of HIPK2. Cell Death Dis. 2021;12(8):747. doi:10.1038/s41419-021-04024-9
8. Ma Z, Wei K, Yang F, et al. Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer. Cell Death Dis. 2021;12(9):840. doi:10.1038/s41419-021-04037-4
9. Chang RM, Fu Y, Zeng J, Zhu XY, Gao Y. Cancer-derived exosomal miR-197-3p confers angiogenesis via targeting TIMP2/3 in lung adenocarcinoma metastasis. Cell Death Dis. 2022;13(12):1032. doi:10.1038/s41419-022-05420-5