There may be a smarter, more effective way to attack mesothelioma — a way that could overcome mesothelioma’s tendency to roar back stronger than ever after it’s removed.
That better way has not yet been identified, but scientists are now on a surer footing to do so, thanks to eye-opening research from the University of Hawaii Cancer Center.
University researchers report in the latest edition of the Journal of Translational Medicine their discovery that mesothelioma starts not with the mutation of a single mesothelial cell but with the mutation of many of them at the same time.
What that means is today’s gene-based mesothelioma therapies are missing the mark.
They miss it by targeting monoclonal mesothelioma cells when they could be scoring bull’s-eyes by instead targeting polyclonal mesothelioma cells.
A polyclonal mesothelioma tumor is a mass consisting of two or more distinctly different cells, each mutated by asbestos exposure but all growing together.
The researchers note that polyclonal mesothelioma cells feature multiple types of mutation. Conventional targeted mesothelioma therapies are designed to attack only one type of mutation.
“Our findings underscore the need to attack simultaneously several different molecular targets,” said lead researcher Michele Carbone, M.D., Ph.D.
He explained that such an attack strategy would seek to eliminate the different malignant mesothelioma cell clones — necessary because each target may carry its own special set of molecular alterations.
Mesothelioma Conventional Wisdom Challenged
The University of Hawaii Cancer Center team explored this business of polyclonal versus monoclonal mesothelioma cells because they suspected the conventional wisdom might be in error.
Conventional wisdom holds that mesothelioma is caused when a single cell mutates. Mesothelioma grows when that lone mutated cell clones itself and then those clones clone themselves, and on and on.
The entrenched belief that most cancers are of monoclonal origin began decades ago, the researchers wrote.
They observed that it “arose primarily from the study of hematopoietic malignancies and sarcomas, which originate as monoclonal tumors.”
The researchers indicated they too had bought into that notion but came to believe mesothelioma is actually caused by mutations in multiple cells.
To test their theory, the researchers examined 16 tissue samples from 14 mesothelioma tumor biopsies.
One of those samples didn’t yield clinically useful information. Nearly all of the other samples showed a pair of electrophoretically distinct methylated HUMARA alleles.
HUMARA is shorthand for the human androgen receptor assay process they used to evaluate the tumor cells. Alleles are gene variants.
Translated into plain English, these electrophoretically distinct methylated HUMARA alleles provided compelling evidence that the mesothelioma tumors in question had a polyclonal origin.
Mesothelioma Exerts a ‘Field Effect’
The researchers concluded that the asbestos fibers trapped inside the lungs of someone who is yet to develop mesothelioma exert a “field effect” — in other words, they mutate more than one cell at once.
Granted, it takes up to 50 years for those asbestos fibers nesting inside the lungs to succeed at bringing about the deadly mutation.
However, when the mutation finally occurs many cells are involved at the same time, the researchers explained.
“It may be possible that more than one cell undergoes malignant transformation during the process that gives rise to malignant mesothelioma, and result in a polyclonal malignancy,” the researchers wrote.
If true that malignant mesothelioma tumors are polyclonal, there could soon be a radical change in everyone’s understanding of the disease and the way it’s treated, the researchers predicted.