The team’s initial inspiration came from their work on lung development. “The tree-like ramification of the papillary bladder tumours have some likeness to the minute branches of the bronchioles in the lungs,” Iber explains. This led them to wonder whether similar molecular mechanisms might be responsible for creating both these structures. Yet subsequent research showed this not to be the case. “It turns out that the molecular drivers in the formation of lung tissue are quite different to those in the development of bladder cancer,” says Iber.
Mechanical, not biochemical
When it comes to lung tissue, a biochemical mechanism defines the position of new branches. In bladder cancer, however, the emergence of papilla appears to be influenced by mechanical rather than biochemical factors. In support of this theory, the Basel-based researchers have now published a study in the form of a preprint – a full draft of a research paper that is shared publicly before peer review.
To understand their theory, it helps to visualise the structure of the bladder wall. This wall is flexible and has numerous folds that enable the bladder to expand and contract depending on the amount of urine it has to hold. Three layers of tissue play an important role here. Together, they make up the innermost layers of the bladder wall, like an onion: first, a soft epithelial layer on the inside of the bladder wall; next, a substantially stiffer membrane, which provides mechanical stability; and, beyond that, a somewhat softer layer of connective tissue.
Based on computer models, biopsies from tumour patients and tissue samples harvested from experiments with mice, the researchers’ theory posits that cancerous growth is accompanied by changes in the relative stiffness of the different layers of the bladder wall. Depending on the degree of these changes, different forms of cancer develop. If there is only a minimal change in the stiffness of the layers relative to one another, blunt protrusions may grow from the bladder wall into the cavity of the bladder. These can then form the basis for papillary tumours. By contrast, if changes in relative stiffness are more significant, the surface of the bladder mucosa remains smooth. Instead, the membrane that separates the epithelium from the surrounding layer of connective tissue forms fine wrinkles and narrow folds. The researchers posit that this can result in tissue damage that encourages the growth of a malignant tumour into the inner layers of the bladder wall.
Focus on the early stages
“Pathologists have described changes in bladder wall stiffness in patients with advanced bladder cancer,” explains Franziska Lampart, a doctoral student in Iber’s group. The Basel researchers now used an animal model to investigate the early stage of bladder cancer. In collaboration with the group led by Daniel Müller, Professor of Biophysics at the ETH Department of Biosystems Science and Engineering, atomic force microscopy revealed localised softening of the membrane layer even at this early stage. “This supports our idea that local changes in the relative stiffness of individual bladder wall layers play an important role in the development of bladder cancer,” says Lampart.
