Abstract
Gastrointestinal malignancies remain among the leading causes of cancer-related morbidity and mortality worldwide, largely due to late diagnosis, aggressive tumor progression, and resistance to conventional therapies. Tumor angiogenesis and the tumor microenvironment (TME) play crucial roles in the initiation, growth, and metastatic dissemination of gastrointestinal cancers. Hypoxia-driven signaling pathways, including hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and inflammatory mediators such as NF-κB and MAPK, are key regulators of these processes. Increasing evidence suggests that natural products derived from medicinal plants and other biological sources may modulate these pathways and exhibit anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. This review summarizes recent findings on natural compounds that influence angiogenesis and tumor microenvironment dynamics through the regulation of molecular pathways involved in hypoxia signaling, extracellular matrix remodeling, fibroblast activation, and inflammatory responses. Compounds such as neotuberostemonine, aloperine, silymarin derivatives, tanshinone IIA, berberine, asiatic acid, and phloretin demonstrate promising biological activities in experimental models by targeting pathways including HIF-1α, PI3K/AKT/mTOR, TGF-β/Smad, and NF-κB signaling. However, further studies focusing on gastrointestinal cancer models and clinical validation are required to translate these preclinical observations into effective therapeutic strategies.