At times, cancer cells break free from a tumor and journey to another part of the body. The “highways” they take for this trip are the body’s circulatory system and other transport networks that reach every corner of the body. Not all cells survive this trip, as they encounter strong mechanical forces due to the flowing fluid and other cells present within the channels.
The mechanical stress generated by the physical forces exerted on these circulating tumor cells can activate cellular pathways that lead to their death. However, a small number possess unique abilities that allow them to adapt and thrive under this mechanical stress, enhancing their chances of survival and ultimately leading to new tumors somewhere else in the body — a phenomenon known as metastasis.
Not every cancer evolves to metastasis, but when it happens, it is often a significant contributor to cancer-related deaths. In many cases, cancer becomes life-threatening when it spreads to vital organs and interferes with their normal functions. At this stage, the cancer can be more challenging to treat, and the prognosis may be less favorable.
Studying the characteristics of tumor cells that can survive these mechanical forces could help us understand the biology of metastasis and develop new therapies to control or fight it.
“The circulating tumor cells are rare in the bloodstream, which makes it challenging to identify and study the properties of the circulating tumor cells,” said Kin Fong Lei, professor in the Department of Biomedical Engineering at the Chang Gung University in Taiwan.
Since isolating and studying these circulating cancer cells from the body is a difficult task, Lei and his team instead built a lab model that mimics the mechanical forces in the bloodstream to pick out the surviving tumor cells and better understand the properties that allow them to survive and propagate in other organs. The results of their study were published in Advanced Biology.
“By comprehending the behavior and properties of these surviving cells, new therapeutic strategies can be potentially developed and enhance cancer treatment outcomes,” said Lei.
Catching the sneaky although dangerous cells
Lei and his team’s system was built using flexible tubes of silicon and other stretchy material that allows gas exchange and mimics the body’s vessels through which liquid representing blood was pumped. The scientists added human cancer cells, and after simulating a trip through the bloodstream, they collected the cells that had survived the ride.
To understand what made these tumor cells special, they first analyzed their genes and surprisingly found they had a similar genetic profile to stem cells.
“Our results showed the surviving tumor cells expressed higher gene expression levels of self-renewal and differentiation markers,” said Lei, which correlates with stem cell-like properties.
Later, Lei’s team tested different functional properties of the surviving tumor cells. They performed experiments in the lab to measure different properties that correlate to their capabilities to form a secondary tumor somewhere in the body.
After comparing with control cancer cells, the team observed that the surviving tumor cells had enhanced capabilities for migration, spheroid formation, and colony formation. “These characteristics indicated the surviving tumor cells have high tumor metastatic potential,” said Lei.
Talking with the immune system
Once the team determined the selected cells had the potential to generate secondary tumors, they analyzed their interaction with cells from the body’s immune system.
Normally, the immune system would attack and destroy circulating cancer cells before they are able to colonize another organ. But this doesn’t always seem to happen, and Lei and his team wanted to determine how these cells might be avoiding detection.
For this, they grew control cancer cells and the surviving cancer cells separately with immune cells called M1 macrophages, which play a role in the body’s defense against infections and in the inflammatory response.
After five days, Lei found that control cells were killed by these macrophages, while the surviving tumor cells had the ability to suppress the M1 macrophage’s function, implying that they have the ability to evade immune surveillance.
Future directions to fight metastasis
With their findings pointing towards the potential link between these surviving tumor cells and the initiation of metastasis, Lei’s team is poised to take the next crucial step. “We are planning to do animal experiments to further confirm the surviving cells have high tumor metastatic potential,” said Lei.
The stem cell-like qualities and immune evasion abilities of surviving tumor cells offer valuable clues, suggesting that the method developed by Lei’s team could be a valuable tool to obtain circulating cancer cells in a sufficient amount in order to study the biology behind metastasis in cancer.
“This study lays the foundation for further investigations and opens doors to innovative interventions aimed at combating metastasis and improving overall patient care,” said Lei.
Reference: Chia-Hao Huang, et. al., Investigation of Stem Cell-Like Characteristics and Immune Cell Interaction of Tumor Cells Survived from Continuous Shear Flow Environment, Advanced Biology (2023). DOI: 10.1002/adbi.202300332
Feature image credit: Shameer Pk on Pixabay