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INTERNATIONAL CONGRESS OF

CancerGenetics

• Physiological Alterations and Gene Regulation in the Tumor Microenvironment

• Seyed Mohammad Kasra Esfahani,¹ Davood Nourabadi,^2,* Kimia Sadat Esfahani,³
  1. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran
  2. Department of Physiology, TeMS.C., Islamic Azad University, Tehran, Iran.
  3. Department of Genetics, Faculty of Advanced Sciences and Technology, TeMS.C., Islamic Azad University, Tehran, Iran
  
  
  
• Introduction: Tumors are among the most significant threats to human health due to their aggressive nature and limited treatment options. Tumors are not isolated masses of proliferative cells but rather exist within a complex and dynamic structure known as the tumor microenvironment (TME). The TME consists of non-malignant stromal cells, extracellular matrix components, blood and lymphatic vessels, and a variety of soluble factors such as cytokines (such as interleukin-6 [IL-6]) and growth factors (such as Transforming Growth Factor β [TGF-β], Vascular Endothelial Growth Factor [VEGF] family). Physiological stresses within the TME—such as hypoxia, nutrient deprivation, and acidosis—induce adaptive responses in both cancer and stromal cells. These stresses drive extensive transcriptional reprogramming, often through by genetic mutations, epigenetic changes, and altered signaling pathways. Oncogenes and tumor suppressor genes may undergo mutations or be epigenetically regulated (silenced/activated), contributing to tumor initiation, progression, and therapy resistance. Increasing evidence suggests that gene regulation under these stressful conditions plays a crucial role in promoting tumor cell proliferation, invasion, immune evasion, and metabolic rewiring. Understanding how physiological alterations modulate gene expression in the TME is essential for identifying new therapeutic targets and improving treatment efficacy.
• Methods: A total of twenty relevant articles focusing on physiological alterations and gene regulation in the tumor microenvironment were identified through systematic searches in PubMed, Google Scholar, and Scopus using predefined keywords. These studies were subsequently selected for in-depth review and analysis.
• Results: The TME is characterized by dynamic physiological and mechanical alterations that profoundly affect tumor behavior and immune responses. Among these, ferroptosis—a regulated form of cell death—has emerged as an immunogenic process. Ferroptotic cells release metabolites and damage-associated molecular patterns (DAMPs) that can activate tumor-infiltrating immune cells, indicating the immunogenic potential of this pathway. In parallel, tumor progression is closely associated with physical remodeling of the stromal compartment, including increased tissue stiffness, solid stress, and elevated interstitial fluid pressure (IFP). These mechanical changes disrupt tissue architecture and impair the function of blood and lymphatic vessels, resulting in poor perfusion and compromised lymphatic drainage. The subsequent rise in IFP enhances interstitial fluid flow (IFF), facilitating the dissemination of tumor-derived factors into surrounding nonmalignant tissues. Mechanical cues arising from solid stress, vascular collapse, and extracellular matrix stiffening play a critical role in regulating cellular responses within the TME.
• Conclusion: Physiological alterations within the tumor microenvironment, including mechanical stresses and biochemical changes, significantly influence gene regulatory networks in both cancer and stromal cells. These interactions promote tumor progression, immune modulation, and therapy resistance. A deeper understanding of the molecular mechanisms linking physical remodeling and gene expression in the TME may provide novel therapeutic targets and improve cancer treatment outcomes.
• Keywords: Gene regulation, Tumor microenvironment (TME), Cancer therapy, Mechanical stress, Ferroptosis