Tunneling Nanotubes: Cellular Highways for Cancer Drug Delivery, Study Suggests

Cancerous tumors are complex. The diseased cells multiply among healthy cells, spread to tissue and leech valuable proteins and nutrients from their surrounding microenvironments.

An emerging pool of evidence shows that cancer cells form miniscule tubes that they use to communicate and shuttle vital signals and nutrients back and forth, making them more aggressive and potentially more resistant to drugs intended to treat cancer. But, new research from the Masonic Cancer Center, University of Minnesota suggests that these tubes may also serve as an ideal pathway to deliver cancer-killing viruses and other drug particles designed to treat cancer.

Called tunneling nanotubes, these exceedingly narrow but long offshoots stem from cancer cells and attach to nearby cells. These tubes then exchange important cellular cargo that are vital to sustaining cancer cells, like mitochondria, proteins, and genetic materials called microRNAs.

Researchers in this growing field had hypothesized that these tunneling nanotubes could also transfer virus-based cancer drugs. A new study in the journal Molecular Therapy – Oncolytics led by Emil Lou, M.D., Ph.D, assistant professor of the University of Minnesota’s Medical School, confirms this idea.

Lou, a member of the university’s Masonic Cancer Center, collaborated with researchers at Memorial Sloan-Kettering Cancer Center and the City of Hope Cancer Center to complete the study. Currently, viral gene therapies – drugs that leverage common viruses like herpes, polio and measles – are engineered to be safe in humans, and are injected into tumors. When the virus infects the cancer cells, it triggers an immune response and kills the cancer.

“The concept of engineering viruses to treat cancer has been around for decades and gained more traction the past few years,” Lou said. “Current forms of viral therapies infects cells and destroy them from the inside out; the viruses then move on to the next set of cells to create a cycle of infection.”

For this study, the researchers used a mutant strain of herpes simplex virus genetically engineered to infect and kill cancer cells, and emit a green fluorescent protein that could be used to track its progress.

They infected mesothelioma cancer cells with the mutant virus. Under a high-resolution microscope, they visualized the glowing virus multiplying in the cancer cells, then saw it move from cell to cell through the tunneling nanotubes.

“Through our experiments, we found that the virus could not only spread from cell to cell via nanotubes, but also that the activated drug could as well,” Lou said. “This dramatically increases the number of cancer cells that could be killed through this combined approach to treatment.”

This behavior has potential implications for the design of new drugs and treatment of cancerous tumors. Lou’s research suggests the cancer cells forming nanotubes may more readily absorb nano-sized drugs and cancer-treating viruses, making them efficient and effective.

These findings indicate the nanotubes can act as auto-routes for drug delivery. If researchers learn more about how and when the nanotubes sprout, they could be used to treat patients with drugs designed to travel through the auto-routes.

“This provides a better picture of how cancerous tumors are constantly evolving, communicating and growing,” Lou added. “By learning about these processes, we can figure out how to either stop the cancer cell communication or make sure the drugs are being circulated throughout the tumors. It’s a good first step to build upon.”

Co-authors of this article with Lou include: Yuman Fong, M.D., from the City of Hope Cancer Center; Justin Ady, M.D., Kelly Mojica, and Joshua Carson, M.D., from Memorial Sloan-Kettering Cancer Center; and Venugopal Thayanithy, Ph.D., Phillip Wong, and Prassanna Rao from the University of Minnesota.