World Cancer Day 2017: Simon Leedham

World Cancer Day takes place on February 4 each year.  NDM researchers are trying to understand the epidemiology and potential causes of cancer, its effect on patient lives and outcomes, as well as the basic science underpinning the unregulated cell growth that is the hallmark of the disease.

To mark World Cancer Day 2017, NDM has asked some of our cancer scientists about their research.

Professor Simon Leedham is a Cancer Research UK Clinician Scientist and an Honorary Consultant Gastroenterologist. His current research focuses on the cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in cancer.

Q: What are intestinal stem cells and why are they susceptible to cancer?

Simon Leedham: Our intestines are organized into millions and millions of tiny flask like structures called crypts and each crypt contains a family of cells. The stem cells reside at the very bottom of these crypts and are like the head of the family. The stem cells divide and give rise to daughter cells, which move up the sides of the crypts. As the daughter cells do this, they specialise to form all of the different cell types needed to digest and absorb our food and water. Because of this constant movement, the average lifespan of a daughter cell is only 5 to 7 days. After this, they die and fall out of the crypts forming part of our stool.

This constant renewal of the lining of our guts helps our bodies to rapidly respond to infection or damage and also provides a very clever protection against cancer. If one of these daughter cells acquires a mistake or mutation in their genetic material (DNA), it doesn’t matter much, as that cell will be dead within 7 days and will never get the chance to form a cancer. The stem cell however, as the head of the family, has a much longer lifespan in its specialized niche at the base of the crypt. If a mutation happens in one of these cells, then cancer is a risk, because not only does the cell survive long enough to eventually develop into a tumour, but it will also pass on that same acquired genetic mistake to all the daughter cells that it gives rise to.

Q: How are these stem cells controlled?

SL: This organised crypt structure and the fate of all the cells in the crypt is very strictly controlled in health to prevent stem cells from dividing too much or too little. Stem cell division and daughter cell fate decisions are regulated by a series of chemical messages. These messages come from a variety of cells in the intestinal wall, including both the stem cells themselves and the supporting cells that surround the crypt. Cancer can arise if the stem cells don’t respond appropriately to the signals they receive and/or if the chemical message delivery goes wrong.

One of the major issues we face in treating established tumours is that a cancer has the ability to corrupt the normal chemical messaging system to suit its own purpose. In this way a cancer can generate and use chemical messages to drive its own cancer cell growth, whilst ignoring all the messages that try to restrain cell division.

Q: Can we improve survival rates for these cancer patients?

SL: My research focuses on these chemical messages that can get co-opted and corrupted by cancer cells. Our work has shown that an imbalance in one of these chemical messaging systems can lead to an increased number of tumour cells behaving like stem cells. This ability of a cancer cell to alter its fate is like a leopard changing its spots, and is known as stem cell plasticity. This isn’t good news: these new stem cells can divide and make new cancer cells. Even if we manage to kill some cancer cells with drugs or radiation treatment, stem cell plasticity allows other cancer stem cells to take their place. We are looking at ways to restore the signaling pathway balance, which we think might allow current anti-cancer treatments to work more effectively and prevent cancer cells from developing rapid drug resistance.