High levels of specific protein may impair high-risk paediatric neuroblastoma

The Umeå University researchers behind the study: Eirini Antoniou, Subhamita Maitra, Johan Holmberg and Caroline Lindehell

ImageOlof Jansson

"The findings increase our understanding of how neuroblastoma develops and can hopefully contribute to new treatments in the long term," says Johan Holmberg, professor of molecular tumour biology at Umeå University and one of the researchers behind the study.

Neuroblastoma is a form of cancer that affects the sympathetic nervous system in young children and is often difficult to treat, especially when the tumour cells have many copies of a gene called MYCN. In the new study, the researchers have focused on a protein called HIF2α.

When the researchers induced high levels of HIF2α in neuroblastoma cells with many copies of the MYCN gene, they could see a sharp decrease in the protein expressed by the MYCN gene. At the same time, the expression of genes typical of cells that produce noradrenaline in the adrenal medulla increased. This suggests that the tumour cells began to resemble more mature cells in the sympathetic nervous system. The cells also stopped dividing as quickly and they developed long protrusions; a sign that they are maturing.

In experiments in a mouse model of neuroblastoma, the growth of the tumours was significantly reduced when high levels of HIF2α were induced. When analysing patient samples from children with neuroblastoma, the researchers found that high levels of the gene, EPAS1, which codes for the protein HIF2α were associated with low levels of MYCN and with genes that are typical of more mature cells. In addition, patients with high levels of EPAS1 generally had a better prognosis.

The study thus challenges a previous view that HIF2α would act as a driver of cancer in neuroblastoma. Instead, the results suggest that the protein may in some cases have a slowing function and promote maturation into less aggressive cells.

"The discovery may prove significant, but there is a long way to go before new treatments based on this can be considered," says Johan Holmberg.

Neuroblastoma accounts for about six percent of cancer cases among children. There are several different degrees of severity of the disease that affect the prognosis. Treatments have improved in recent decades so that three out of four children affected survive the disease. However, survival is unfortunately worse for patients with many copies of the MYCN gene.

The study, which is supported by the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Kempe Foundation and the Faculty of Medicine's Strategic Research Resource at Umeå University, is published in the scientific journal PNAS.