This newly published review article offers a comprehensive examination of the complexities of tumor angiogenesis and the origins of endothelial cells (ECs) within tumors. Tumor angiogenesis, a critical process in cancer progression, is characterized by the formation of new blood vessels that sustain tumor growth by supplying oxygen and nutrients. Understanding the diverse sources and mechanisms of endothelial cell development is essential for improving anti-angiogenic therapies, which aim to block blood vessel formation and, consequently, hinder tumor proliferation.

This review delves into the origins of endothelial cells in both normal and tumor angiogenesis, revealing that while normal angiogenesis is typically a structured and regulated process, tumor angiogenesis is notably chaotic and disorganized. Tumor vascular endothelial cells (ECs) arise from various sources, including adjacent ECs, bone marrow-derived endothelial progenitor cells (EPCs), and even cancer stem cells, which can differentiate into endothelial-like cells. Additionally, cancer-associated fibroblasts and immature dendritic cells may transdifferentiate into vascular ECs within the tumor microenvironment.

The article highlights that the dysregulation and heterogeneity of tumor blood vessels complicate the development of effective therapies. Although anti-angiogenic agents have been a pivotal element in cancer treatment, the limited efficacy and resistance of these therapies pose significant challenges. The review outlines the mechanisms of drug resistance, which include adaptive angiogenesis, alternative pathway activation, and genetic heterogeneity within endothelial cells. This resistance often results in the incomplete inhibition of blood vessel growth, allowing tumors to adapt and continue proliferating.

By investigating the molecular signaling pathways involved in tumor angiogenesis, including VEGF, PDGF, FGF, and ANG/Tie2 systems, the article underscores the importance of targeted therapeutic approaches that account for the diverse cellular origins and adaptive mechanisms of tumor endothelial cells. Innovations in therapy must consider the heterogeneous nature of tumor vasculature to overcome resistance and enhance clinical outcomes.

This review offers a nuanced understanding of endothelial cell biology in tumors. By focusing on the origins and adaptive mechanisms of tumor vasculature, it sets the stage for the development of more precise and effective therapeutic strategies to combat cancer.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Yulong Han, Binqiang Zhu, Shu Meng, Endothelial cell in tumor angiogenesis: Origins, mechanisms, and therapeutic implication, Genes & Diseases, Volume 12, Issue 6, 2025, 101611, https://doi.org/10.1016/j.gendis.2025.101611

Funding Information:
National Natural Science Foundation of China 82170512
Major Project of Guangzhou National Laboratory of China GZNL2023A02009