Recent research has unveiled that DNA secreted by tumor cells through extracellular vesicles (EVs) can stimulate an immune response that helps inhibit the spread of tumors to the liver. This significant finding, led by researchers from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Korea's Yonsei University, enhances the understanding of cancer progression and the body's immune mechanisms against cancer.

The study, which appears in Nature Cancer, investigates how cancer cells release short strands of DNA encased in EVs. All cell types utilize EVs to transport proteins, DNA, and other molecules, with tumor cells exhibiting particularly high levels of EV secretion. The precise biological roles of EV-packaged molecules are still under investigation, but this research indicates that the DNA released by tumor-derived EVs acts as a 'danger' signal that triggers an anti-tumor immune response within the liver, thereby reducing the likelihood of liver metastasis.

Initial hypotheses suggested that increased levels of tumor EV-DNA would correlate with poorer patient outcomes. However, findings revealed a contrary relationship, as higher levels of EV-DNA were associated with better prognoses.

Dr. David Lyden, a leading figure in the study, noted that prior investigations had shown that tumor cells release snippets of EV-DNA containing cancer-specific mutations. In this comprehensive study, researchers discovered an unexpected arrangement of EV-DNA, which was found primarily on the surfaces of the EVs, complexed with histone proteins, similar to the structure found in chromosomes. This structural configuration suggests that EV-DNA may possess unique signaling capabilities.

The research team identified multiple genes involved in the regulation of EV-DNA packaging and found that the absence of one gene, APAF1, significantly reduced the quantity of EV-DNA secreted by tumor cells. Earlier studies indicated that cancer cells could secrete proteins and fatty acids that enhance the liver's environment for tumor development. Consequently, researchers anticipated that tumor-secreted EV-DNA would similarly promote metastasis.

Contrary to this expectation, experiments conducted on animal models of pancreatic and colorectal cancers demonstrated that elevated levels of tumor EV-DNA resulted in reduced metastasis risk. In contrast, genetic deletion of APAF1 led to a marked increase in metastatic risk.

Moreover, in colorectal cancer patients, those exhibiting low EV-DNA levels at diagnosis were found to have a higher likelihood of developing liver metastases compared to those with elevated EV-DNA levels.

The research team also determined that liver-resident immune cells, known as Kupffer cells, absorb the tumor EV-DNA. These immune cells are activated by specific markers of damage present in the EV-DNA, prompting them to form clusters that resist the spread of tumors to the liver. This represents a previously unrecognized tumor-suppressing mechanism, suggesting that cancers capable of downregulating EV-DNA secretion may have an enhanced ability to metastasize.

Moving forward, the research team aims to create a prognostic test based on EV-DNA levels to predict the risk of metastasis, along with developing a potential vaccine-like therapy designed to amplify EV-DNA signaling and mitigate metastasis in patients diagnosed with early-stage cancer.

This research not only broadens the scientific understanding of cancer biology but also opens avenues for new clinical tools and therapies aimed at improving patient outcomes in cancer treatment.