Researchers have screened 20,000 molecules to
discover a potent compound with low toxicity that restores the balance of
healthy stem cells in the lungs of mice.
A molecule identified by researchers through
screening helps maintain a healthy balance of cells in airway and lung tissue.
According to the scientists, if the compound, so far only studied in isolated
human and mouse cells, has the same effect in people, it may lead to new drugs
to treat or prevent lung cancer.
“We think this could help us develop a new
therapy that promotes airway health,†said Dr Brigitte Gomperts, lead author of
the study and professor of paediatrics and pulmonary medicine at the University
of California LA (UCLA), US, where the stiudy was conducted. “This could not
only inform the treatment of lung cancer, but help prevent its progression in
the first place.â€
The human respiratory system is regularly
replenished with healthy cells. That process is driven by airway basal stem
cells, which divide to produce both more stem cells and the mucociliary cells
that line the airways and lungs.
Mucociliary
cells include:
mucus cells, which produce the mucus that
trap toxic and infectious particles
ciliated cells, which have finger-like
projections that sweep the mucus away to keep the respiratory system healthy
and clear.
In healthy lungs, airway basal stem cells
stay balanced between producing mucociliary cells and self-renewing to maintain
a population of stem cells. In pre-cancerous cells in the lungs, basal stem
cells divide more often than usual, generating a large number of stem cells but
too few mucociliary cells. The resulting imbalance of cells in the airway
leaves it unable to properly clear debris and creates a greater risk that the
pre-cancerous cells will develop into a tumour.
In the new study, the researchers analysed
airway cells from equal numbers of biopsies of healthy people, patients with
pre-malignant lung cancer lesions and patients with squamous lung cancer. They
discovered that one group of molecules – collectively called the
Wnt/beta-catenin signaling pathway – was present at different levels in the
basal stem cells of the patient samples versus the cells from healthy people.
Normal airway tissue, left and lung cancer
tissue, right
Normal airway tissue, left and lung cancer
tissue, right, with an overabundance of basal stem cells (green). The activated
form of beta-catenin (red) in the lung cancer can be targeted by the Wnt
Inhibitor Compound 1 (credit: Broad Stem Cell Research Center).
Altering the levels of these molecules in
healthy airway cells from mice, the team found the balance between stem cells
and mucociliary cells shifted, mimicking the imbalance seen in lung
pre-cancers.
“When you activate the Wnt/beta-catenin
signaling pathway, these stem cells just divide and divide,†said Gomperts.
Finally, the researchers screened more than
20,000 chemical compounds using high-throughput methods. They investigated
their ability to reverse this effect in human cells, lowering levels of Wnt and
restoring the balance of stem cells and mature airway cells.
One compound, named as Wnt Inhibitor Compound
1 (WIC1), was particularly effective at limiting the proliferation of basal
stem cells and restoring the balance of the stem cells and mucociliary cells to
regular levels. The researchers also noted that the compound was less toxic to
airway cells than previously discovered molecules that block Wnt/beta-catenin
signalling.
“The identification of this new drug is a nice tool to tease apart the biology of the Wnt/beta-catenin signalling pathway and its effects on lung health,†said Cody Aros, the first author of the new paper and a UCLA graduate student. “It’s also very exciting that it may act in a new way than other existing Wnt/beta-catenin signalling pathway inhibitors and has such low toxicity.â€
As WIC1 was identified through a random drug screen, the researchers do not yet know exactly how it works, but they are planning future studies on its mechanism and safety.
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