The epithelial variant of malignant peritoneal mesothelioma is characterized by molecular changes that give stem cell properties to the cancer cells and promote resistance to cancer drugs, according to a study by Italian researchers.
The study, “Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework,“ was published in the journal Oncotarget.
Mesothelioma is a cancer arising in the mesothelium, the membrane lining several body cavities. Earlier research has shown that a process termed “mesenchymal-epithelial reverse transition” likely is a key mechanism in the development of the cancer, and all three types of asbestos are known to trigger the transition.
Mesenchymal and epithelial cells are relatives, and the conversion between the two cell types is crucial during development, and is needed for wound healing. Both the conversion of epithelial to mesenchymal cells, and the reverse process of mesenchymal cells taking on epithelial properties, have been linked to cancer.
Recent studies have shown that when the transition is not complete, it gives rise to cells that possess a mix of traits linked to the two processes. Such cells behave more like stem cells, are highly adaptable, and have more mechanisms by which they develop resistance to cancer treatment.
Researchers at the Istituto Nazionale dei Tumori in Italy suspected that the epithelial variant of peritoneal mesothelioma is characterized by such a halfway transition.
The research team analyzed tissue samples obtained during surgery of 21 untreated patients with malignant pleural mesothelioma. Using an array of methods to study the molecular properties of the tumors, the study found that epithelial mesothelioma tumors, including the high-grade undifferentiated form, are characterized by the presence of the factors that are associated with tumor stem-cell properties, including a capacity to be highly adaptable.
To test whether the presence of these factors did give the tumor these properties, the research team also used tissue from the tumors to grow cells in the lab. Experiments confirmed that the cells behaved like stem cells, and changed their appearance in response to treatment.
When researchers challenged the cells with the immune factors TGF-beta1 and IL-1, the tumor cells became more mesenchymal-like. Instead, exposing cells to the hepatocyte growth factor HFG made them take on a more epithelial-like appearance.
The researchers believe this is occurring through modification in the DNA (epigenetic changes) caused by the EZH2 protein, which is the active subunit of a DNA and histone methylation complex. Indeed, EZH2 was found to be increased upon TGF-beta1 and IL-1 exposure, but decreased upon HGF stimulation, suggesting that this protein may be targeted in the tumor.