The Role of Cell Compaction in Radiation Therapy for Breast Cancer

Abstract

Physical compaction and accompanied collagen remodelling are required for normal organ development, while tumour cell compaction induces tumour angiogenesis and growth by changing expression of an angiogenic factor, Vascular Endothelial Growth Factor. Tumour cell compaction is involved in the resistance to chemotherapy in ovarian and breast cancer, and to radiotherapy in colon cancer. Here, we show that the modification of physical cell compaction, which changes the tumour microenvironment, is able to improve the response and to decrease resistance to radiotherapy in breast cancer. To investigate whether mechanical compression of breast cancer cells alters their response to irradiation, we first examined the effects of irradiation on 4T1 breast cancer cells in vitro. Irradiation of 4T1 cells causes DNA fragmentation 4 h after irradiation, which is partially recovered 24 h later. The expression of Platelet Derived Growth Factor-b (PDGF-b) decreases in the cells 4 h post-irradiation, while this decrease is attenuated 24 h after irradiation, suggesting that PDGF-b may mediate this recovery from radiation-induced DNA damage by increasing resistance. We then explored whether mechanical compression and subsequent changes in ECM structure contribute to these effects by plating breast cancer cells at different densities or by compressing tumour tissues in vitro. Tumour compression inhibits DNA fragmentation in vitro by stimulating a rise in PDGF-b expression, and treating the cells with a PDGF inhibitor hinders this resistance. These findings suggest that manipulation of mechanical forces such as tumour cell compaction could improve tumour response to radiotherapy through PDGF-b signalling.