Stromal-derived high-molecular-weight hyaluronan mediates radioresistance in the prostate cancer microenvironment

Radiotherapy (RT) is a key treatment for localized prostate cancer (PCa); however, resistance and recurrence remain major challenges. Hyaluronan (HA), a key component of the extracellular matrix, has been implicated in cancer progression and therapeutic resistance. However, its role in the modulation of radiosensitivity, particularly in the tumor microenvironment, remains unclear. In this study, we aimed to investigate the role of HA in the radiosensitivity of PCa cells.

22Rv1 PCa epithelial cells and WPMY-1 myofibroblast cells were cultured to mimic tumor-stroma interactions. The effect on radiosensitivity was evaluated using colony formation assays. HA levels and molecular weight from cell culture supernatants were analyzed using enzyme-linked immunosorbent assays and agarose gel electrophoresis. Hyaluronidase expression was assessed using quantitative RT-PCR.

WPMY-1 cells exposed to supernatants had significantly higher HA secretion than 22Rv1 cells. WPMY-1-derived HA enhanced the radioresistance of 22Rv1 cells, which was reversed by hyaluronidase. HA induced by 22Rv1-derived factors appears to be necessary for colony formation. The induced HA showed a shift toward a higher molecular weight owing to the downregulation of the degrading enzymes Hyal1 and PH20. The molecular weight of HA played a key role in modulating these effects.

Our findings suggest that stromal cells may contribute to the radioresistant tumor microenvironment in PCa partly through alterations in high-molecular-weight HA. While targeting HA metabolism holds potential to improve the efficacy of RT by disrupting this protective niche, further studies are needed to clarify the underlying mechanisms and validate these effects in vivo.