Evidence that metastases arisede novoas new cancers from cells of target organs

Abstract

AbstractIntroductionBased on our earlier report that cell-free chromatin particles (cfChPs) released from dying cancer cells are potentially oncogenic, we hypothesised that metastases arise as new cancers from the cells of target organs transformed by cfChPs released from dying cancer cells.MethodsWe intravenously injected MDA-MB-231 human breast cancer cells and A375 human melanoma cells into mice with severe combined immunodeficiency. In separate experiments, we intravenously injected purified cfChPs isolated from radiation-killed MDA-MB-231 cells.ResultsWe observed that the injected MDA-MB-231 and A375 cells died upon reaching the lungs, and released cfChPs that accumulated in the lung cell nuclei at 48 h. We detected the activation of 10 hallmarks of cancer and immune checkpoints in lung cells at 72 h, suggesting that the lung cells had rapidly transformed into incipient cancer cells. Metaphase preparations and single-cell clones developed from cell cultures of lung metastases that subsequently developed contained chimeric chromosomes of both mouse and human DNA, and the cells co-expressed both human- and mouse-specific proteins. The Intravenously injected purified cfChPs isolated from radiation-killed MDA-MB-231 cells also induced lung metastasis containing chimeric chromosomes and co-expressing proteins.DiscussionThese results provide evidence to suggest that cfChPs released from dying cancer cells integrate into genomes of target cells to transform them into new cancers which masquerade as metastasis. They support our hypothesis that metastases arise from the cells of target organs and not from cells derived from the primary tumour. These findings have implications for therapeutic policies for cancer.