Molecular 'switch' in cancers of testis and ovary discovered

An 'on/off' switch in a type of cancer which typically occurs in the testes and ovaries has been identified by Cambridge scientists.
Malignant germ cell tumours arise in sperm- or egg-forming cells and usually occur in the reproductive organs, the testes or ovaries. The cancerous tumours are seen in patients of all ages, both in childhood and adulthood.
Although many patients do well after treatment, current chemotherapy treatments can have severe long-term side effects, including hearing loss and damage to the kidneys, lungs and bone marrow.
The scientists found that all malignant germ cell tumours contain large amounts of a protein called LIN28. This results in too little of a family of tiny regulator molecules called let-7. In turn, low levels of let-7 cause too much of numerous cancer-promoting proteins in cells.

Importantly, the cancer-promoting proteins include LIN28 itself, so there is a vicious cycle that acts as an 'on' switch to promote malignancy.
The researchers have likened these changes to a 'cascade effect', extending down from the large amounts of LIN28 to affect many properties of the cancer cells.

The researchers also discovered that by reducing amounts of the protein LIN28, or by directly increasing amounts of let-7, it is possible to reverse the vicious cycle.
Both ways reduced levels of the cancer-promoting proteins and inhibited cell growth. Because the level of LIN28 itself goes down, the effects are reinforced and act as an 'off' switch to reduce cancerous behaviour.

"We need new ways of treating patients with malignant germ cell tumours, to minimise the toxic effects of chemotherapy and to improve survival rates when tumours are resistant to treatment," Nick Coleman, Professor of Molecular Pathology, Cambridge University said.
"Having identified this 'on/off' switch, it will now be important to identify new drugs that can be used to keep it in the 'off' position," he said.
"The switch effect that we have discovered is present in all malignant germ cell tumours, whether they occur in males or females, young or old. Such a fundamental abnormality makes an excellent new target for treating these tumours," said Dr Matthew Murray, Academic Consultant in Paediatric Oncology, Addenbrooke's Hospital, Cambridge.

The study was published in the journal Cancer Research.