One of the latest developments in killing cancer cells involves using ultrasound waves, typically used in medical imaging. Ultrasound therapy for cancer uses sound waves to disrupt cancer cell membranes. Unlike normal cells, cancer cells lack some of the repair mechanisms that protect a normal cell against damage. The lack of repairability makes them more vulnerable to specific treatments, such as low-frequency ultrasound waves, which can potentially cause cell death. The method is appealing due to its noninvasive nature and cost-effectiveness.
However, the effectiveness of ultrasound therapy can vary depending on the type of cancer and its location in the body. This variability and how different cancer cells respond to mechanical forces may require tailoring treatments to individual patients.
Researchers from the Indian Institute of Science (IISc) and the National University of Singapore have been trying to improve the effectiveness of ultrasound therapy. A new study shows how subtle nanoscale changes can enhance ultrasound treatments' effectiveness in killing cancer cells.
Their work focuses on subtly changing the Extracellular matrix (ECM), a 3D network of proteins and other molecules that surrounds and supports cells and tissues. The ECM is like a web that surrounds cells, providing physical support. The surface of the ECM also provides binding spots for cell receptors known as integrins. Integrins are proteins that help cells attach to each other and the ECM.
In healthy tissues, the spaces between the binding points on the ECM are around 50 to 70 nanometers (nm) apart. However, in cancerous environments, things get a little more crowded. Excess ECM causes these spaces to shrink below 50 nm. This increased density affects how the cancer cells interact with the ECM, influencing how they respond to treatments.
“We found more cancer cells being killed when the binding spacing is increased to around 50-70 nm,” remarks Ajay Tijore, Assistant Professor at IISc and corresponding author of the study.
The study mimicked the integrin-ECM binding in the lab using arrays of gold nanoparticles separated by different distances—35 nm, 50 nm, and 70 nm. Then, invasive cancer cells were allowed to grow on these arrays. Pulsed ultrasound waves were then applied to these cells to study their effectiveness in disrupting them.
The study found that when cancer cells were grown on arrays with 50 nm and 70 nm spacings, their cell membranes stretched under the influence of a protein called myosin, leading to an influx of calcium into the cells. This calcium influx disrupted the mitochondria, eventually causing the cells to die. However, at 35 nm spacing, the cells couldn't bind as effectively. They failed to generate the necessary myosin forces, leading to a reduced response to the ultrasound waves. All they had to do was increase the spacing between the cancerous cells so that the ultrasound waves could destroy the cells effectively.
In an interesting turn of events, the researchers discovered an unexpected ally in the drug Cilengitide.
“While doing these experiments, we stumbled upon literature on a drug called Cilengitide. It was one of the most widely studied drugs and went to Phase III clinical trials, but it failed," explains S Manasa Veena, PhD student at IISc and first author of the study.
Cilengitide targets integrins to block their binding to the ECM. When used in extremely low doses with ultrasound treatment, Cilengitide was surprisingly effective. There weren’t enough drug molecules at low doses to bind all the integrin receptors. This lack of receptors tricked the cancer cells into perceiving the 35 nm spacing as if it were in the more effective 50 to 70 nm range.
“We are fooling the cancer cell into thinking that the spacing has changed. Now the cell starts developing myosin forces, pumps more calcium inside, and this triggers cancer cell killing,” explains Prof. Tijore
The research highlights how small changes at the nanoscale level can lead to significant advances in cancer treatment. By understanding the complex ways cancer cells interact with their environment and harnessing those interactions with precision, we can potentially improve treatments and reduce side effects.
Currently, the team is working with clinicians to apply these findings to oral cancer, a significant health challenge in the Indian subcontinent.
“Oral cancer is a major problem in the Indian subcontinent. There is a lot of ECM deposition, leading to swelling, inflammation … and extreme choking of the tumour microenvironment. This is what we are currently working on.” remarks Prof. Tijore.
This research news is based on a Press Release from Indian Institute of Science (IISc)
This research news was partly generated using artificial intelligence and edited by an editor at Research Matters