Treatment Slows Tumor Growth in New Lung Cancer Subtype

A subtype of human adenocarcinoma has been identified that could help determine which individuals are at a greater risk of developing lung tumors that may be responsive to new therapy, a recent study found.

Previously, study authors demonstrated that non-small cell lung cancer (NSCLC) tumor cells frequently expressed too little, or none at all, of the transcription factor C/EBPα. During their prior work, scientists hypothesized that C/EBPα may act as a tumor suppressant in normal cells.

However, the mechanisms by which its absence promote lung cancer tumors was unclear. In a study published in Science Translational Medicine, researchers set out to figure out how.

“Advances in lung cancer therapy require a great understanding of the molecular origins of this deadly disease,” said lead researcher and last corresponding study author Elena Levantini, PhD. “Understanding the differences among lung cancers also could lead to innovations in treatment strategies and allow up to overcome drug-resistance, relapse, and disease progression.”

In the current study, researchers performed a series of in vitro experiences to help demonstrate that C/EBPα does in fact act as a tumor suppressant by restraining the expression of the oncogenic protein BMI1, which is known to play a role in triggering and maintaining tumor growth and has been implicated in colon cancer. To find the relationship between C/EBPα and BMI1, researchers genetically altered a line of human adenocarcinoma cells so that they overexpressed C/EBPα.

This resulted in the marked reduction in the expression of BMI1. Next, researchers analyzed tissues from 261 NSCLC patients.

The results of the study showed an inverse correlation between the 2 molecules; more than 80% of patient tissues with low levels of C/EBPα were positive for BMI1 expression. When an analysis was performed on tissues samples from lung adenocarcinoma patients with no or low C/EBPα expression, researchers found that patients who had lower levels of BMI1 were more likely to survive.

“Our findings suggest that the lung cancer subtype defined by the loss of C/EBPα expression might specifically benefit from therapies that inhibit BMI1,” the study authors wrote. “Thus identifying factors that modulate its expression has generated major clinical interest.”

When researchers performed their findings on mice, they were able to further validate their results. One set of experiments involved mice that were engineered to express no C/EBPα.

This resulted in an inverse relationship between the transcription factor and BMI1 that was nearly identical to data found from the human adenocarcinoma. After manipulating the oncogenic protein expression in vivo, researchers could confirm that by decreasing the expression of BMI1, it was enough to fully inhibit the formation of the lung cancer tumor and even arrest tumor growth.

“BMI1 plays a substantial role in many solid tumors, including one of the most aggressive models of lung cancer, and its expression is linked with tumor growth, invasion, metastasis, prognosis, and recurrence,” Levantini said. “Our findings could help us design better therapies for the subset of adenocarcinoma patients with low C/EBPα and high BMI1 expression pattern.”