Researchers at UCLA have identified a molecule that plays an important role in the homeostasis of airway and lung tissue, helping to ensure there is a healthy balance of stem cells and mature lung cells. This molecule is the only one that has been studied in isolated human and mouse cells. It could prove to be invaluable in the treatment of lung cancer and could potentially be harnessed to prevent lung cancer from developing in the first place.
The cells in the airways and lungs need to be constantly replenished due to constant injury from airborne pollution and pathogens. Basal stem cells in the airways are critical to the repair process. The basal stem cells can divide to produce new stem cells and can differentiate into mucociliary cells – the cells that form the lining of the airways that trap particles and pathogens.
Mucociliary cells are divided into two types: Mucus cells and ciliated cells. The mucus cells produce mucus that traps particles as they enter the airways and the ciliated cells have cilia – finger-like protections – that sweep the mucus away to keep the airways clear.
A healthy respiratory system is perfectly balanced, with the basal stem cells producing new mucociliary cells and self-renewing at an optimal level. In precancerous cells this balance is upset. Basal stem cells divide to create too many stem cells and not enough mucociliary cells and, as a result, the lungs become less effective at clearing debris and pathogens. That increases the risk of precancerous cells becoming cancerous and forming tumors.
The researchers performed an analysis of airways cells taken from healthy patients, patients with premalignant lung cancer lesions, and patients with squamous lung cancer and identified a group of molecules that are present at differing levels between the three groups of patients. Collectively, these molecules were named the Wnt/beta-catenin signaling pathway.
The researchers manipulated the levels of the molecules in the airways cells of healthy mice and found that the balance of stem cells and mucociliary cells shifted towards the imbalance seen in precancerous cells, indicating that when the Wnt/beta-catenin signaling pathway was activated, stem cells start to divide uncontrollably.
The researchers then screened more than 20,000 compounds to identify one that was capable of reversing this effect and restoring the balance of stem cells and mucociliary cells and lowering the level of Wnt. They identified a compound that blocked Wnt/beta-catenin signaling – Wnt Inhibitor Compound 1 (WIC1) – which was less toxic than other previously identified compounds known to affect Wnt/beta-catenin signaling.
This compound could potentially be used to promote lung health in lung cancer patients; however, since the compound was identified in a random screening, its method of activity is not yet known and it has only been used in preclinical tests, so it is not yet known if it will be safe and effective for use in humans.
You can read more about the research in the paper – High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis – which was recently published in the journal Cell Reports. DOI: 10.1016/j.celrep.2020.01.059