A stress-adaptive framework for selective exosomal miRNA export in gastrointestinal tumorigenesis

Circulating microRNAs (miRNAs), particularly those associated with extracellular vesicles and exosomes, are widely investigated as minimally invasive biomarkers in gastrointestinal (GI) tumorigenesis, including premalignant and early-stage disease. However, their biological interpretation remains a major unresolved challenge, as circulating and exosomal miRNA profiles frequently diverge from tumor tissue expression patterns, even in early lesions with minimal tumor burden. Here, we propose that this discordance may represent not merely a methodological limitation but also a biologically meaningful feature associated with stress-adaptive cellular processes. Integrating clinical observations with emerging insights into cellular stress responses, exosome biogenesis, and miRNA sorting mechanisms, we present a unifying framework in which regulated, selective export contributes to circulating exosomal miRNA profiles alongside passive release and other extracellular RNA sources. In premalignant and early malignant GI lesions, convergent stressors, including hypoxia, metabolic limitation, oxidative and endoplasmic reticulum stress, and oncogene-induced replication stress, reshape vesicular trafficking and RNA-binding protein-mediated sorting machinery. These processes dynamically reprogram exosomal miRNA composition, generating circulating signatures that reflect stress-adaptive states rather than static tumor identity. We further integrate extracellular signaling and the proposed intracellular relief function of exosomal miRNA export into a unified stress-adaptive model, offering a potential mechanistic explanation for the early emergence, tissue-circulation discordance, and temporal evolution of circulating miRNA biomarkers. This perspective reframes circulating exosomal miRNAs as dynamic readouts of stress adaptation, with direct implications for biomarker interpretation, risk stratification, and longitudinal monitoring in GI tumorigenesis.