# Proteomic insights into the invasiveness and tumor progression of non‐functioning pituitary adenomas: A scoping review

## TL;DR

This review explores proteomic studies of non-functioning pituitary adenomas to identify biomarkers and pathways linked to tumor invasiveness and progression.

## Contribution

The paper provides a comprehensive synthesis of proteomic findings in non-functioning pituitary adenomas, highlighting potential biomarkers and dysregulated pathways.

## Key findings

- Altered extracellular matrix remodeling and dysregulated PI3K–Akt and MAPK/ERK signaling are associated with NFPA invasiveness.
- Recurrent alterations in MAPK/ERK, PI3K–Akt–mTOR, Wnt/β-catenin, and IL6/JAK/STAT3 signaling suggest interconnected pathways drive NFPA biology.
- Most studies had small sample sizes and methodological heterogeneity, limiting the establishment of robust biomarkers.

## Abstract

Nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors that, despite being histologically benign, can exhibit invasive growth, as well as postoperative tumor progression. Surgical resection is the primary treatment of choice; however, residual tumor tissue is frequently observed, with between 30% and 50% of these cases subsequently experiencing regrowth. The molecular mechanisms governing NFPA behavior remain poorly understood, and robust prognostic biomarkers are still lacking despite genomic and transcriptomic studies. Mass spectrometry (MS)‐based proteomics enables large‐scale, global protein quantification and monitoring of changes in protein expression, which could identify markers of tumor behavior as well as potential new therapeutic targets. This review synthesizes existing proteomic research on NFPAs and identifies candidate biomarkers and dysregulated pathways associated with invasiveness and tumor progression. We used PubMed, the Cochrane Library, and Scopus to perform a structured and comprehensive literature search of studies published since the year 2000 that applied MS‐based proteomics to evaluate NFPAs. The identified studies were grouped into three main categories: (1) proteomic differences between NFPAs and normal pituitary glands, (2) biomarkers linked with tumor progression, and (3) molecular signatures distinguishing invasive from noninvasive NFPAs. Among the 30 included studies, 15 compared NFPAs with normal pituitary tissue and reported altered protein expression, metabolic reprogramming, and spliceosome dysregulation. Only two studies addressed tumor progression, showing associations with RNA processing, energy metabolism, and β‐catenin phosphorylation. Studies evaluating NFPA invasiveness (n = 16) highlighted altered extracellular matrix remodeling and dysregulated PI3K–Akt and MAPK/ERK signaling along with specific proteins, including Ezrin and β‐catenin. Across themes, recurrent alterations in MAPK/ERK, PI3K–Akt–mTOR, Wnt/β‐catenin, and IL6/JAK/STAT3 signaling suggest that NFPA biology is driven by interconnected pathways rather than isolated molecular events. Sample sizes were generally small, with more than 50% of studies analyzing less than 10 NFPAs, and only one study including up to 100 NFPAs. Methodological heterogeneity and lack of validation remain major limitations. Although modern proteomic studies provide valuable insights into NFPA biology and particularly invasiveness, investigations on mechanisms of progression are limited. Moreover, robust biomarkers have not yet been established, and most findings remain exploratory due to small sample sizes and methodological heterogeneity. Future research should focus on larger, prospective cohorts, integration of clinical and imaging data with multi‐omics approaches, and standardized protocols for sample handling and preparation to enhance reproducibility. Such efforts are needed to translate proteomic discoveries into clinically useful biomarkers and novel therapeutic strategies.