# Uterine Stroma-Derived Tumors and the Extracellular Matrix: A Comparative Review of Benign and Malignant Pathologies

## TL;DR

This paper reviews how the extracellular matrix influences the development and progression of uterine stromal tumors, from benign to malignant forms.

## Contribution

The paper provides a comparative review of ECM's role in uterine stromal tumors, highlighting its potential as a biomarker and therapeutic target.

## Key findings

- ECM molecules like collagens and proteoglycans influence tumor architecture and progression.
- ECM remodeling enzymes create a pro-tumorigenic environment linked to invasion and resistance.
- ECM alterations intersect with angiogenesis and immune evasion in uterine sarcomas.

## Abstract

Uterine stromal-derived tumors, rare neoplasms, range from benign endometrial stromal nodules to aggressive high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas. Endometrial stromal tumors localize in the hormone-responsive connective tissue of the endometrium, the uterus’s inner layer. This review summarizes the classification of these tumors based on molecular and immunohistochemical profiling. Furthermore, the existing knowledge on the role of the extracellular matrix in the biology of endometrial stromal tumors is described. Although ECM’s importance in the normal uterus has been widely studied, its role in endometrial cancer is limited. Modulation of ECM molecules, including collagens, proteoglycans, and glycosaminoglycans, as well as matricellular enzymes, has been shown to remodel stromal architecture and influence tumor formation, function, and cancer development. The presented evidence suggests that ECM molecules may serve as diagnostic and prognostic biomarkers, as well as targets for therapy in uterine sarcomas. Understanding the ECM-driven mechanisms of these challenging tumors may ultimately improve their classification, prognosis and treatment.

Uterine stromal-derived tumors encompass a spectrum of rare neoplasms, ranging from benign endometrial stromal nodules to aggressive high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas. The classification of these tumors has advanced through molecular and immunohistochemical profiling, but the role of the extracellular matrix (ECM) in their biology is only beginning to be understood. The ECM provides both structural support and dynamic signaling cues, regulating tumor cell proliferation, invasion, angiogenesis, and immune evasion. Altered expression of collagens, proteoglycans, glycosaminoglycans, and matricellular proteins reshapes stromal architecture and contributes to disease progression. Moreover, ECM remodeling enzymes such as matrix metalloproteinases, together with cross-linking factors, create a stiff and pro-tumorigenic microenvironment that facilitates invasion and therapeutic resistance. Furthermore, these matrix alterations intersect with angiogenesis, mechanotransduction pathways, and immune modulation. Studies to date describe the role of ECM molecules in the function of the physiological uterine tissue and data for the uterine stroma-derived tumors is scarce. This review summarizes the existing knowledge in classification, prognosis and diagnosis, and summarizes the ECM-driven mechanisms in tumors described so far, aiming to identify new and prognostic biomarkers and novel therapeutic targets in uterine sarcomas.