# Can Cancer Cell Line In Vitro Radioembolization Model Help to Understand How Beta Radiation Affects Liver Tumor and Improve Treatment Results?

## TL;DR

This study uses an in vitro model to explore how beta radiation from 90Y-microspheres affects liver tumor and healthy cells under different oxygen conditions.

## Contribution

The study introduces an in vitro model to investigate the effects of beta radiation on cancer and healthy liver cells under normoxic and hypoxic conditions.

## Key findings

- Hypoxia reduces sensitivity to 90Y radiation and promotes a pro-angiogenic tumor environment.
- HCT 116 and THLE-2 cells show radiosensitivity, while HepG2 cells are more resistant to radiation.
- Radiation effects vary by cell type and oxygen levels, influencing apoptosis and angiogenic signaling.

## Abstract

Radioembolization with 90Y-labeled microspheres is an established locoregional therapy for primary and metastatic liver tumors, yet the molecular mechanisms underlying tumor response and resistance, particularly within hypoxic tumor microenvironments, remain poorly understood. Here, we developed an in vitro model of 90Y-microsphere irradiation to investigate the effects of beta radiation under normoxic and hypoxic conditions in human colon cancer (HCT 116), hepatocellular carcinoma (HepG2), and non-malignant liver (THLE2) cell lines. Cells were exposed to two microsphere dilutions, and absorbed doses were estimated using FLUKA-based Monte Carlo simulations. Cellular viability, proliferation, apoptosis-related gene expression, and secretion of angiogenic and inflammatory mediators were assessed. 90Y-microspheres exerted both cytotoxic and cytostatic effects in a cell type- and oxygen-dependent manner. In HCT 116 cells, radiation reduced metabolic activity and proliferation and induced Bax expression in normoxia, whereas hypoxia conferred radioresistance associated with Bcl-2 upregulation. HepG2 cells displayed pronounced resistance, with preserved viability but marked inhibition of proliferation, indicating a predominantly cytostatic response that was further attenuated by hypoxia. In contrast, THLE-2 cells were radiosensitive, showing reduced proliferation and increased Bax expression, while hypoxia partially protected against radiation-induced damage. Both hypoxia and microsphere exposure promoted a pro-angiogenic phenotype, characterized by increased VEGF secretion in radiosensitive tumor and healthy cells, whereas resistant HepG2 cells exhibited angiogenic signaling linked to TIMP2 suppression and IL-8 induction. Collectively, our findings demonstrate that hypoxia diminishes cellular sensitivity to 90Y beta radiation while fostering a microenvironment conducive to tumor progression. This in vitro model provides mechanistic insight into radioembolization responses and may support the development of more personalized therapeutic strategies.