Low-dose Photon Irradiation May Help Malignant Mesothelioma Cells Spread, German Study Warns

Low-dose photon irradiation, commonly used in radiotherapy, potentially helps malignant pleural mesothelioma (MPM) cells spread, warns a study by Germany’s University of Heidelberg.

The study, “Low-dose photon irradiation induces invasiveness through the SDF-1α/CXCR4 pathway in malignant mesothelioma cells,” appeared in the journal Oncotarget. It was based on research led by Dr. Stefan Rieken of the university’s departments of thoracic surgery and radiation oncology.

Despite significant research, no definite treatment guidelines have been established for MPM. Multimodality therapy regimens using chemotherapy, radiotherapy or surgery have yielded only minor improvements. In addition, local relapse of MPM often occurs after the multimodality approach.

Radiotherapy routinely uses photon beams. Modern techniques within photon irradiation have enabled specific targeting of tumors while sparing healthy tissues. More recently, a new modality – particle irradiation – has been proposed to replace photon irradiation, with dose-escalated treatments further reducing damage to healthy cells.

However, studies in other types of cancer including lung cancer, prostate cancer and melanoma have shown that low doses of photon irradiation can promote cellular migration and propagate tumor infiltration. These tumor recurrences occur mainly within areas of prior photon exposure.

Researchers hypothesized that mesothelioma cells might migrate from radiation targets before administration of lethal doses. A tiny protein involved in immune response, the chemokine SDF-1α, has often been implicated in radiation-induced motility involving thoracic cancers.

The study tested the ability of two different MPM cell types to proliferate indefinitely — thereby retaining their reproductive abilities — and to migrate with and without various doses of photon and carbon ion irradiation.

The authors determined levels of several proteins, including SDF-1α and its ligand CXCR4, using molecular biology techniques. 

Results showed that SDF-1α stimulated the migration of MPM cells. Low doses of photon irradiation kept cells from proliferating, but stimulated their migration through the SDF-1α/CXCR4 molecular pathway by increasing the levels of CXCR4. The team managed to stop migration using a CXCR4 antagonist — a molecule that binds to a receptor and prevents its activation.

In contrast, corresponding low doses of carbon ion irradiation suppressed the proliferation of cells but did not promote migration.

The study’s results demonstrate photon irradiation’s failure to control MPM. In addition, the relationship between MPM and the SDF-1α/CXCR4 pathway is in line with previous findings.

Overall, “our findings suggest that the co-administration of photon irradiation and the CXCR4-antagonist AMD3100 or the use of carbon ions instead of photons may be possible solutions to reduce the risk of locoregional tumor recurrence after radiotherapy for MPM,” the researchers wrote.

The results still need validation in vivo, and further studies are required to evaluate tumor irradiation’s effects on the microenvironment surrounding the tumors, and to determine additional molecular pathways involved in cell motility in MPM, authors wrote.

Nevertheless, the results warrant clinical trials for carbon ion irradiation, as it presents “higher relative biologic effectiveness in tumor cell killing and a more accurate dose distribution, which contributes to the low risk of side effect,” compared to photon irradiation, they added.