Hypoxia-Induced Extracellular Vesicles and Non-Coding RNAs in Cancer: A Systematic Review of Tumor Dynamics and Therapeutic Implications in Preclinical Animal Models

Background: Cancer is a heterogeneous pathology, and among causative factors, gene expression can influence its development. Molecular approaches using extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) offer great value in understanding tumor progression, early diagnosis, and potential therapies. Objectives: This systematic review was conducted in accordance with the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses guidelines. Its main objective was to evaluate the effects of cellular hypoxia in different types of cancer, exclusively using animal models and highlighting the regulatory role of microRNAs and circular RNAs in tumor development. Methods: A literature review was performed using the PubMed/Medline and Scopus databases without year limitations. The initial search yielded 171 articles. After applying the inclusion and exclusion criteria, 25 studies were included in this review. Data analysis showed that animal models provide detailed insights into different types of cancers under hypoxic conditions. Results: Our analysis identified that specific circRNAs, such as circPFKFB4 in breast cancer and circPDK1 in pancreatic cancer, are consistently associated with a worse prognosis and therapeutic resistance. Similarly, miRNAs such as miR-1287-5p (breast cancer) and miR-133a (colorectal cancer) have frequently been identified as tumor suppressors whose levels are altered by hypoxic conditions. Furthermore, the results suggested that in some cancers, the release of EVs may facilitate tumor progression and metastasis. However, manipulation of ncRNA expression causes significant changes in the tumor response, which suggests a therapeutic response. Conclusions: This study shows that the use of animal models is essential for exploring the molecular mechanisms of cancer and establishing new therapeutic approaches.