Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes

by Gorantla V. Raghuram, Kavita Pal, Gaurav Sriram, Afzal Khan, Ruchi Joshi, Vishalkumar Jadhav, Sushma Shinde, Alfina Shaikh, Bhagyeshri Rane, Harshada Kangne, Indraneel Mittra

Metastatic dissemination following successful treatment of the primary tumour remains a common cause of death. There is mounting evidence that therapeutic interventions themselves may promote development of metastatic disease. We earlier reported that cell-free chromatin particles (cfChPs) released from dying cancer cells are potentially oncogenic. Based on this observation we hypothesized that therapeutic interventions may lead to the release of cfChPs from therapy induced dying cancer cells which could be carried via the blood stream to distant organs to transform healthy cells into new cancers that would masquerade as metastasis. To test this hypothesis, we generated xenografts of MDA-MB-231 human breast cancer cells in severe combined immune-deficient mice, and using immuno-fluorescence and FISH analysis looked for cfChPs in their brain cells. We detected multiple human DNA signals representing cfChPs in nuclei of brain cells of mice which co-localized with eight human onco-proteins. No intact MDA-MB-231 cells were detected. The number of co-localizing human DNA and human c-Myc signals increased dramatically following treatment with chemotherapy, localized radiotherapy or surgery, which could be prevented by concurrent treatment with three different cfChPs deactivating agents. These results suggest that therapeutic interventions lead to the release cfChPs from therapy induced dying cancer cells carrying oncogenes and are transported via the blood stream to brain cells to potentially transform them to generate new cancers that would appear as metastases. cfChPs induced metastatic spread of cancer is preventable by concurrent treatment with agents that deactivate cfChPs.