A mouse model has shown how one type of cancer turns into another
Lung tumors called adenocarcinomas in some cases respond to initially effective treatment by transforming into the much more aggressive small cell lung cancer, which spreads rapidly and has few treatment options. The researchers developed a mouse model to uncover the mechanisms of this histologic transformation.
Cancer cells continue to evolve to escape the pressures of effective treatments. For example, small cell lung cancer is most common in avid smokers, but also develops in patients with lung adenocarcinomas. It is especially common after treatment that targets a protein called the epidermal growth factor receptor. Newly mutated tumors like small cell lung cancer are resistant to therapy against this receptor because their growth is "fueled" by a new cancer-causing factor, high levels of the Myc protein.
Some oncogenes, such as the epidermal growth factor receptor gene and Myc, normally control cell growth, but in mutants are known for their role in promoting cancer growth and spread. Tumor suppressor genes, on the other hand, stop cell division and further cancer progression.
The researchers, whose work is published in the journal Science, found that in the transition from lung adenocarcinoma to small cell lung cancer, the mutated cells undergo a change in cellular identity through an intermediate stem cell-like state. The scientists engineered mice with a common form of lung adenocarcinoma in which lung epithelial cells are driven by a mutated version of the epidermal growth factor receptor gene.
The scientists then turned the adenocarcinoma tumors into small cell lung cancer tumors, which normally arise from neuroendocrine cells. They did this by turning off the epidermal growth factor receptor gene and tumor suppressor genes (Rb1 and Trp53), and by increasing the activity of the Myc gene, which encodes a protein of the same name.
During the transformation process, the researchers found an intermediate stem cell-like stage that was neither adenocarcinoma nor small cell lung cancer. Cells in this transitional state acquired a neuroendocrine nature only in the presence of mutations in two genes, tumor suppressors. Loss of another suppressor accelerated the process. In this case, oncogenic Myc triggered the transformation of intermediate stem cells into small cell lung cancer.
The study showed that oncogenes act in a context-dependent manner. While most lung cells are resistant to becoming cancerous due to the Myc protein, neuroendocrine cells are highly sensitive to its oncogenic effects. Conversely, the epithelial cells that line the air sacs of the lungs and act as precursors to lung adenocarcinomas overgrow in response to the mutated epidermal growth factor receptor gene.
The new scientific work was another in a piggy bank of targeting Myc family proteins that are involved in many types of cancer. Scientists have been able to explain how mutated cancer cell genes trigger the development of a new type of cancer and suggest targets for more effective therapies.
The researchers now plan to use the new mouse model to further study the transition of adenocarcinoma to small cell lung cancer, detailing, for example, how the immune system usually responds to this transition.