Beclin-1 as an autophagy biomarker in colorectal cancer

Colorectal cancer (CRC) is the leading cause of cancer-related morbidity and mortality attributable to cancer worldwide. Therefore, there is still a need for strong biomarkers that can be used to assist with the diagnosis, prognostication, and therapeutic stratification of patients. The role of autophagy in CRC development is context-dependent, and Beclin-1 is a major controller of autophagy initiation, which has been suggested as a potential biomarker for CRC. However, its regular use in clinical practice has been inhibited by inconsistent clinical correlations and high methodological variability. This is a review of Beclin-1 as a laboratory-measurable analyte, not as a mechanistic autophagy marker, or as an element of clinical chemistry and diagnostic pathology processes. We provide an overview of the biological properties of Beclin-1 directly associated with the interpretation of biomarkers, such as its functional complexes, regulatory changes, and context-related functions in tumor biology. Specific attention is given to specimen types and pre-analytical variables, such as tissue handling, fixation conditions, ischemia time, and intratumoral heterogeneity, which may contribute remarkably to the measured Beclin-1 levels. Existing measurement methods, such as immunohistochemistry, protein-based assays, transcriptomic, and exploratory analysis of extracellular vesicles, are discussed in terms of their application of antibody specificity, assay reproducibility, normalization methodologies, and inter-observer variability. We also addressed the major validation criteria to be specific, precise, linear, and harmonized, as well as available clinical validation data between Beclin-1 expression and tumor stage metastasis, survival, and response to treatment. Finally, the clinical utility and reporting of Beclin-1 in pathology and clinical laboratory processes were also considered, revealing the limitations and future demands for standard implementation.