Cancer rarely kills unless it evolves the ability to spread beyond the tissue in which it developed, to grow into surrounding healthy tissues. An important roadblock for tumor spread is membranous scaffolding, basement membrane, which lines epithelial cell layers in tissues.
Normal epithelial cells and even early-stage tumor cells remain tightly tethered to basement membrane, which segregates healthy and likewise cancerous epithelial cells from surrounding tissues. Breakdown of this barrier allows tumor cells to escape from the tethers of the epithelium, launching a tumor invasion to healthy tissues.
– If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment, says Professor Zena Werbfrom UCSF.
In this study, the researchers led by Dr. Juha Klesfröm from the University of Helsinki, identified a molecular pathway in breast tumor cells leading to activation of a protein-cleaving enzyme hepsin on the surface of breast tumor cells. Tumor cells use hepsin to chop basement membrane proteins – to break free from ties and matrix binding them to local neighborhood in their native epithelial tissue.
M.Sc. Johanna Partanen, a graduate student in the research group of Dr. Klefström, designed and led experiments that resulted in the discovery of a biochemical chain of events that is likely to be initiated by many breast tumor cells when they become invasive.
Partanen found that shutdown of gene Lkb1 disturbs development of parts of the mammary gland, including milk-secreting tissue structures. Especially, basement membrane, which normally surrounds tissue structures of the mammary gland was damaged and degraded.
A culprit for basement membrane damages was pinpointed: Lkb1 shutdown disconnected hepsin from normal regulation and the protein mistakenly started to blanket the surface of mammary epithelial cells, causing degradation of the basement membrane.
Researchers found that inactivation of hepsinallowed the basement membrane to recover. These events may take place in many tumors, as the research found that Lkb1 is missing and hepsin is abnormally expressed in 1 out of 4 human breast cancer samples.
Will these findings help us to fight cancer? – Maybe, says Klefström:
– Hepsin is of a type of protein known as a protease and proteases have been successfully targeted in drug development. We found that deactivation of hepsin in the mammary gland organoids prevents formation of a cancerous phenotype. This finding leads us to think that inhibition of Hepsin by drug-like molecules could restrain breast cancer progression. However, we do not know yet if we can cure already formed tumors by blocking hepsin activity.
The study was published in the Proceedings of the National Academy of Sciences (PNAS).