With 45 annual fatalities/million population and 1/212 male lifetime risk, asbestos is the UK’s leading occupational killer. The UK banned asbestos-containing building materials in 1999, yet 1.5 million buildings, including 94% of hospitals, 80% of schools, and 74% of universities, contain up to six million tons of asbestos.
Passive exposure to asbestos-containing buildings perpetuates MPM in teachers and nurses, who have a five- and three-fold higher risk of Mesothelioma.
The UK Health & Safety Executive acknowledges that legislation barring new asbestos usage will reduce mesothelioma by 2035, however it does not account for passive exposure from pre-1999 building.
Without government action to remove all asbestos from UK buildings, the expected reduction is unlikely. In asbestos-using countries with insufficient labor protection, mesothelioma rates are rising rapidly.
Mesothelioma is difficult to diagnose, delaying treatment.
Mesothelioma slowly forms a large multifocal zone of malignancy that resembles benign pleural inflammation on the chest cavity lining.
No precursor lesion has been found, and molecular diagnostics cannot replace a pathologist’s microscopic tissue analysis. Thus, Mesothelioma diagnosis relies nearly entirely on manual detection of tissue-penetrating cells.
False negatives can happen from many chest endoscope biopsies missing invasive cells. If samples show no invasive sickness, international recommendations advocate observation rather than therapy because only 12-15% of pleural inflammation individuals develop Mesothelioma within two years.
Thus, this “watch and wait” approach prevents timely treatment of early-stage Mesothelioma patients at high risk or those missed at biopsy. Develop diagnostic techniques to identify low-risk inflammation from high-risk pre-malignancy to allow early treatment, which has improved survival in malignant illness patients.
How Mesothelioma mouse models help
Asbestosis symptoms can occur 40 years after exposure, before mesothelioma. However, animal studies show that asbestos fibers in the chest cavity generate persistent inflammation from symptomatic sickness and Mesothelioma.
Mesothelioma frequently occurs in the final mile of a long journey, and victims are symptom-free until advanced. What happens between exposure and symptom manifestation is poorly understood clinically.
My lab generated genetically modified mice models of mesothelioma with persistent inflammation by controlled introduction of human mutations and a single asbestos injection to fill this gap.
One microgram of asbestos (one-millionth of a gram) promotes malignancy in all our animals, indicating that asbestos-driven inflammation is essential to Mesothelioma growth beyond mutagenesis.Our mice models resemble human mesothelioma in microscopic appearance, molecular characteristics, and clinically relevant therapeutic response, showing their importance.
Their highly reproducible, genetically accelerated cancer development allows us to examine the entire disease process from exposure and the first cancer-causing mutations to deadly malignancy.
Our rodent models reveal cancer growth stages that Mesothelioma-prone humans cannot.
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Knowing risk biology
Some mutant combinations produce Mesothelioma in 100% of mice (full penetrance) while others generate varying malignancy (partial penetrance, indicating risk).
Knowing that mice with entirely penetrant mutation combinations develop Mesothelioma lets us collect tissue before symptoms manifest and compare it to fully formed tissue to detect changes. By knowing how long Mesothelioma takes to form in entirely penetrant mice, we may compare samples from partially penetrant animals at the same time following tumor beginning (under experimental control).
We can separate high-risk pre-malignancy from lower-risk pre-cancerous lesions. These comparisons’ molecular and cellular features identify human asbestosis patients’ Mesothelioma-risk samples.
We have tissue and pleural fluid samples from up to 500 symptomatic Mesothelioma-risk individuals, as well as follow-up samples from those who progress and those with stable non-progressing benign sickness.
Cross-species comparisons will enable us find molecular traits that can definitively separate high-risk from low-risk Mesothelioma development, allowing early treatment of high-risk patients and reassuring low-risk individuals.
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