New Delhi: Every day, cells lining our intestine are damaged and replaced. The body has a built-in repair system that helps the gut make new cells when old or damaged ones are lost. Scientists have now identified a protein called ZFP36L2, or ZFP, that plays a central role in this repair process.
But the catch is, colorectal cancer cells can hijack the same mechanism to spread to new organs through a process called metastasis, in which cancer cells break away from the original tumour and travel through the body to grow in distant organs.
Researchers at New York’s Memorial Sloan Kettering Cancer Center (MSKCC), who did the study published 5 August in the science journal ‘Nature’, describe ZFP as a “molecular switch”. It helps mature cells temporarily become more like stem cells so the gut can repair itself after injury.
Stem cells are cells that can keep dividing and produce different types of cells needed by the body.
The researchers found that colorectal cancer cells can use this same ability. When cancer cells leave the original tumour and reach another organ, they need to adapt to their new surroundings and start growing again; becoming more flexible and stem cell-like may help them survive this process.
When researchers removed the ZFP protein from colorectal cancer cells, the cells had difficulty establishing new tumours in distant organs in mice.
“This is really a critical process that works the same way across many different tissues, allowing cells to detect damage and turn on stem cell renewal programmes,” said physician-scientist Karuna Ganesh, senior author of the study.
The new findings on ZFP’s central role in this process could also help scientists develop new treatments, said the study lead author Qingwen Jiang, a postdoctoral researcher at MSK’s Sloan Kettering Institute.
“Our findings suggest that if ZFP can be disrupted in metastatic cancer cells, it could compromise their ability to start new tumors in other parts of the body,” Dr Jiang says.
The study offers new insights into how colorectal cancer spreads and changes in ways that can help it resist treatment. The researchers also found that this family of proteins may play a similar role in other types of cancer.
Dr M. D. Ray, Professor and senior surgical oncologist at the Dr B. R. A. Institute Rotary Cancer Hospital, AIIMS New Delhi, said, “This is an important advance in our understanding of colorectal cancer metastasis and tumour-cell plasticity.”
Tumour-cell plasticity refers to the ability of cancer cells to change their characteristics or state depending on the conditions around them.
He added that the finding could be particularly relevant to micrometastatic disease, where very small deposits of cancer cells remain in the body after treatment and may later grow into detectable tumours.
But he cautioned that the research is still at the laboratory stage. “The discovery is highly promising, but currently remains translational/preclinical and should not yet alter standard colorectal cancer surgery or systemic therapy,” Dr Ray said.
How did the researchers find this?
The researchers conducted a series of experiments in mice and lab-grown tissue to understand how ZFP helps the gut repair itself and how cancer uses the same process to spread.
First, they damaged the intestinal lining of mice and compared animals with and without ZFP. Mice without ZFP had more difficulty repairing the damage, showing that the protein is important for gut repair.
They then grew tiny lab models of healthy gut and colorectal cancer tissue, called organoids, using mouse and human cells. They removed ZFP from these models to see what happened. The experiments showed that ZFP helps cells regain stem cell-like properties that allow damaged tissue to regenerate.
The researchers then tested whether ZFP also helps cancer spread. They injected human colorectal cancer cells, with and without ZFP, into mice and checked whether the cells could form new tumours in organs such as the liver and lungs. Cancer cells without ZFP were much less able to establish new tumours, suggesting that the protein helps cancer cells survive and grow after spreading.
How colorectal cancer cells use process to spread faster
The intestine is constantly repairing itself. Normally, stem cells in the intestinal lining make new cells to replace old or damaged ones.
But when an injury destroys many stem cells, some mature cells can step in. They first enter a temporary stress state because the tissue has been damaged. To help repair the tissue, these cells need to switch off this stress response and become more like stem cells again.
The researchers found that ZFP helps switch off this stress response. This allows the mature cells to become more like stem cells and help repair the damaged intestine.
But cancer cells can use the same process to spread faster.
When colorectal cancer cells spread to another organ, they face a new environment and need to adapt to survive. The researchers found that ZFP helps these cancer cells become more like stem cells, allowing them to survive and grow at the new site.
During the experiment, when ZFP was removed, the cancer cells were much less able to form new tumours in other organs in mice.
Dr Tanuja Shet, Professor of Oncopathology at Tata Memorial Centre in Mumbai, said this ability to change their state helps cancer cells adapt when they reach a new organ.
“Tumours lose this stem cell-ness, go to a new site and they regain their stem cell-ness. At the site of the metastasis, or where the cancer has spread, it regains its plasticity and produces a new tumour there,” she said.
Could targeting ZFP help stop cancer from spreading?
The findings raise the possibility of targeting ZFP to stop colorectal cancer cells from adapting and forming new tumours after they spread. But this is still early-stage research.
The researchers found that removing ZFP can stop cancer cells from forming new tumours in distant organs. However, they also found that losing ZFP in a primary tumour can make some cancer cells more adaptable and resistant to treatment. In about 5 percent to 10 percent of colorectal cancers, ZFP is already mutated or missing. These tumours can develop unusual cell types that are linked to treatment resistance and poorer outcomes.
Dr Shet cautioned that targeting ZFP may not be straightforward. Cancer cells can change their behaviour when one pathway is blocked and may find another way to survive.
“More than blocking ZFP, we need to do something more to make sure that the plasticity of the cell does not go beyond the realm of what we can treat,” she said.
She said ZFP could also be used as a marker of aggressive cancer if scientists develop a test to measure its levels.
The researchers, however, are exploring whether ZFP can be disrupted quickly enough to prevent cancer cells from adapting to the stress of spreading.
“If you very quickly disrupt ZFP—instead of allowing the tumor to slowly adapt over time—the cancer cell loses its ability to manage that stress. It basically self-destructs,” Ganesh said.
The researchers stressed that turning these findings into a treatment will require more work. For now, the study mainly helps explain how cancer cells change their state to survive and spread.
The same family of proteins may also play a role in other cancers. But Dr Shet said researchers will need to establish whether the mechanism works in the same way in cancers of other organs.
“In cancer research, we first identify a gene or protein in one cancer, then study it in other cancers to see whether the same mechanism works. It may not work in the same way in breast, lung or liver as it does in gastrointestinal cancers, because stem cell activity differs between organs,” she said.
(Edited by Viny Mishra)
Also read: Study probes how intestine repairs damaged tissue