New drug kicks the cancer stem cell addiction

Did you know that cancer stem cells have an addiction problem? This might sound bizarre, but the science checks out.

Cancer stem cells are found in many different types of cancer tumors. They have the uncanny ability to survive even the most aggressive forms of treatment. After weathering the storm, cancer stem cells are able to divide and repopulate an entire tumor and even take road trips to create tumors in other areas of the body.

How cancer stem cells are able to survive and thrive is a question that is being actively pursued by scientists who aim to develop new strategies that target these cells.

Cancer stem cells have a Wnt addiction

To understand why a cancer stem cell is so good at staying alive and creating new tumors, you need to get down to the protein signaling level, which is basically a cascade of protein interactions that begin at the cell surface and instruct certain activities inside the cell. During embryonic development, one of the signaling pathways that’s activated is the Wnt pathway. It’s responsible for keeping embryonic stem cells in a pluripotent state where they maintain the ability to become any cell type.

As embryonic stem cells mature into adult cells, Wnt signaling plays different roles. It helps stem cells differentiate or change into cells of various tissues and helps maintain the health and integrity of those tissues. Because Wnt signaling has varying functions depending on the developmental stage of the cells, it’s important for cells to properly regulate this pathway.

It turns out that cancer stem cells don’t do this. Typically cells need to receive certain biochemical signals to activate the Wnt pathway, but cancer stem cells acquire genetic mutations and evolve such that this pathway is constantly activated. They ramp up their Wnt signaling and never turn it off. This “Wnt addiction” allows them to stay alive and flourish in a cancerous stem cell state.

Kicking the Wnt Addiction

A team at the Max Delbruck Center (MDC) in Germany decided to kick this Wnt addiction and make cancer stem cells go cold turkey. They published their results in the journal Cancer Research this week.

Their strategy involved targeting proteins called transcription factors, the activators of genes, that are turned on during aberrant Wnt signaling in cancer stem cells. The transcription factor they focused on is called TCF4. In normal cells, biochemical signals are required to activate the Wnt cascade and a protein called beta-catenin, which transmits signals to transcription factors like TCF4 that then turn on genes. In cancer stem cells, this signal isn’t required because the Wnt pathway is permanently switched on leaving TCF4 free to activate genes that promote tumor cell survival and growth.

The researchers thought that if they could break up the partnership between beta-catenin and TCF4, that they might be able to block Wnt signaling and kill the life-line of the cancer stem cells. They screened a library of drugs and identified a small molecule called LF3 that was able to block the interaction between beta-catenin and TCF4.

A new drug kills that cancer stem cells. The image on the left shows beta catenin (red) in cell nuclei indicating that these are cancer stem cells. The image on the right shows that the new substance sucessfully removed beta catenin from the nuclei. Picture by Liang Fang for the MDC

Cancer stem cells express beta-catenin shown in red on the left. On the right, drug treatment blocks Wnt signaling and removes beta-catenin from the cancer stem cells. (Image: Liang Fang for the MDC)

The scientists tested the LF3 molecule in mice with tumors derived from human colon cancer stem cells. Senior author on the study, Walter Birchmeier, explained in an MDC press release:

Walter

Walter Birchmeier

“We observed a strong reduction of tumor growth. What remained of the tumors seemed to be devoid of cancer stem cells – LF3 seemed to be powerfully triggering these cells to differentiate into benign tissue. At the same time, no signaling systems other than Wnt were disturbed. All of these factors make LF3 very promising to further develop as a lead compound, aiming for therapies that target human tumors whose growth and survival depend on Wnt signaling.”

Upon further analysis, they found that LF3 prevented cancer stem cells from dividing into more stem cells and migrating to other tissues. Instead, they differentiated into non-cancerous tissues. Importantly, the drug did not negatively affect the function of healthy cells nearby. This is a logical concern as Wnt signaling is activated in healthy adult tissue, just in a different way than in stem cells.

This study offers a new angle for cancer treatment. Not only does LF3 force cancer stem cells to kick their “Wnt addiction”, it also spares healthy cells and tissues. This drug sounds like a promising option for patients who suffer from aggressive, recurring tumors caused by cancer stem cells.


 

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