# Prolyl 3-Hydroxylase 2 Supports a Pro-Angiogenic Milieu Promoting Colorectal Cancer Progression and Metastasis

## TL;DR

This study shows that P3H2 promotes colorectal cancer progression and metastasis by altering the tumor environment and increasing blood vessel density.

## Contribution

The study repositions P3H2 as a pro-angiogenic factor in colorectal cancer, revealing its role in tumor microenvironment remodeling.

## Key findings

- P3H2 transcript levels are reduced in colon adenocarcinoma and further decreased in metastatic lesions.
- P3H2 overexpression enhances cellular invasion and increases lung metastases in vivo.
- P3H2 modifies Collagen IV, leading to increased vessel density in the tumor microenvironment.

## Abstract

Prolyl 3-hydroxylase 2 (P3H2) is a key enzyme involved in the architecture of the extracellular matrix (ECM). While previously shown to be regulated by VEGF-A and to play a role in angiogenesis, its function in cancer remains ambiguous. While characterized as a tumor suppressor, its precise function in colorectal cancer (CRC) progression is poorly defined. Bioinformatic analysis and patient data reveal that P3H2 transcript levels are significantly reduced in colon adenocarcinoma tissues, showing a progressive decline in metastatic lesions. Furthermore, VEGF-A exposure upregulates P3H2 transcripts in the HCT116 CRC cell line. To investigate its impact in CRC, we generated a stable HCT116 clone overexpressing P3H2. In vitro studies demonstrated that while P3H2 overexpression inhibited anchorage-independent growth, it significantly enhanced cellular invasion without altering cell proliferation. In vivo, however, P3H2-overexpressing tumors exhibited accelerated tumor growth and a statistically significant increase in lung metastases. P3H2 overexpression remodeled the tumor microenvironment (TME) by modifying its main substrate, Collagen IV, resulting in the induction of increased vessels density. Our study repositions P3H2 as a dynamic enzymatic switch within the TME. This work identifies P3H2-driven ECM remodeling as a promising therapeutic axis in advanced CRC, with particular relevance for combination strategies targeting angiogenesis.