Key mechanism in embryonic development makes colorectal cancer more aggressive, study finds microbiologystudy

Tumor cells in colorectal cancer exploit an important signaling pathway that normally controls embryo development. Researchers have now shown how a protein that controls the development of the arms and heart contributes to making colorectal cancer cells more aggressive and likely to spread.

By understanding these mechanisms, researchers can find ways to fight cancer without damaging vital stem cells. The study, led by researchers at Linköping University in Sweden, has been published in the journal Proceedings of the National Academy of Sciences.

Cancer cells are cells that are misregulated. But they do what healthy cells can normally do under certain conditions.

“Cancer cells don’t invent new functions. For example, the ability of cancer cells to rapidly multiply is also a typical characteristic during the developmental stage, when the embryo grows from a single cell to billions of cells over a short period,” says Claudio Cantù, professor of cell and molecular biology at Linköping University, who led the study.

He is a researcher in developmental biology and has for several years studied one of the most important signaling pathways during embryo development: Wnt signaling.

Wnt is a molecule that cells can secrete to communicate with another cell, which then changes its behavior—often by forming new cells faster. Wnt plays a critical role during this period of cell life. If the signaling is switched off, the organism stops developing.

But Wnt signaling also has a role in cancer, and that is a negative one. Around 8 in 10 cases of colorectal cancer occur because the cell loses control of the Wnt signaling pathway. When Wnt activity is too high, the cell divides uncontrollably.

Unfortunately, it is extremely difficult to turn off Wnt signaling in the body with therapeutics because the same molecule also has an indispensable role in the body’s regulation of normal cell growth. Some types of cells, such as red blood cells and intestinal cells, are constantly made and replaced. The old cells that die must be replaced by stem cells forming the right amount of new cells.

“Wnt is overactive in colon and rectal cancer, so if we could block Wnt, the cancer would theoretically be cured. But, at the same time, the treatment would kill stem cells in the intestine and the person would die even faster than they would have done with the tumor. So, is it possible to block the Wnt signal without doing harm?” asks Cantù.

Yes, maybe. The researchers behind the study have added an important piece to this puzzle. During embryo development, Wnt cooperates with a protein called TBX3, which controls the development of the legs, arms and heart.

In other words, if the TBX3 gene is damaged by mutations, it leads to defects in various organs, such as the heart and limbs. Cantùs’s research group has previously discovered that this cooperation between Wnt and TBX3, somewhat surprisingly, also occurs in cancer cells in the large intestine.

“It’s a universal mechanism and for me there’s an inherent beauty in discovering how it works. For example, TBX3 controls the formation of the limbs of humans and all other vertebrates, and it controlled the same processes in the dinosaurs. But it’s also important to understand this mechanism, because in this study we found that TBX3 activates genes that make colorectal cancer more prone to spread,” says Cantù.

The researchers show that various molecular interactions are necessary for TBX3’s ability to make cancer cells more likely to form secondary tumors, or metastases, that spread throughout the body. The discovery opens up opportunities to develop therapeutics that target these interactions and prevent tumor cells from spreading.

“Our new findings also indicate that TBX3 is important for the cancer cell, but not for normal stem cells in the intestine. The discovery means that it may be possible to inhibit TBX3 in cancer cells without harming the patient,” says Cantù.

The research project is an international collaboration between researchers in Sweden, Japan, Russia and Switzerland.