Endogenous modulators in lung cancer

Abstract

This editorial aimed to consolidate current evidence on the role of major endogenous modulators—nitric oxide (NO), prostaglandins (PGs), thromboxanes (TXs), and endothelins (ETs) in the lung carcinogenesis, their receptor-specific actions, compensatory feedback mechanisms, and their role in tumor immune evasion and angiogenesis. We searched PubMed and Google Scholar with free-text and MeSH combinations of terms including "lung cancer", "nitric oxide", "inducible NOS", "COX-2", "prostaglandin E₂", "thromboxane A₂", "endothelin", "angiogenesis", and "immunosuppression". We examined English-language publications for mechanistic data, preclinical models, and clinical correlates, and synthesized findings from both animal and human tissue studies. We highlight here the dual, concentration-dependent actions of NO, PG-E2's immunosuppressive and pro-angiogenic actions via E-Prostanoid (EP2/EP4) receptors, thromboxane A₂'s pro-metastatic functions by thromboxane receptor signaling and interaction with platelet-tumor interaction, and the underappreciated roles of ETs. We also point to gaps in the existing literature on the differential roles of other prostanoid subtypes (e.g., PGI2, PGD2), hypoxia-inducible factor-1α's role in regulation of inflammatory cascades, and clinical significance of compensatory upregulation of TX synthase following cycloxygenase-2 inhibition. These observations underscore the potential need for receptor-targeted therapies, biomarker-guided patient stratification, and improved translational models to inform the development of personalized anti-inflammatory interventions in lung cancer.

Keywords: Lung cancer; Nitric oxide; Prostaglandins; Thromboxanes; Tumor microenvironment; Angiogenesis; Biomarkers; Cyclooxygenase

Core Tip: Endogenous mediators—nitric oxide, prostaglandin E₂, thromboxane A₂, and endothelins—induce lung tumor angiogenesis, immune escape, and metastasis through crosstalk signaling loops; targeting their individual receptors and employing eicosanoid biomarker profiles for patient stratification could enable more effective, patient-specific anti-inflammatory therapies in lung cancer.