Landmark study reveals novel mechanism controlling human tumour growth

Research published in Cancer Research on Wednesday (1 October) reports that messenger RNAs derived from two entirely normal genes, CYCLIN D1 and TROP2, can be joined to form a new hybrid molecule that causes cancer.

Researchers from the Unit of Cancer Pathology, University of Chieti, Italy, discovered a novel mechanism of induction of tumour growth in man. The team, lead by Prof Saverio Alberti, have demonstrated that messenger RNAs derived from two entirely normal genes can be joined to form a novel hybrid molecule, that causes cancer.

CYCLIN D1 is a master controller of cell proliferation, and TROP2, discovered by the Alberti’s team, has been sown to be widely overexpressed in cancers and to stimulate their growth, as reported to the public at the European Cancer Conference (ECCO 14) in Barcelona 2007.

The chimeric RNA is generated by an as yet unknown mechanism. This stimulates the growth of cancer cells, being unrestrained by the normal mechanisms that regulate RNA stability and activity rather than by generating abnormal proteins.

The tumours that mainly express the chimeric RNA are cancers of the stomach, colon, ovary, uterus and kidney, together with a small subgroup of breast cancers.

This discovery debunks the idea that all tumours originate from alterations of DNA, e.g. mutations of driver genes, called oncogenes.

Professor Alberti said: “These results open unexpected perspectives. Tumour prevention has been traditionally based on the prevention of the occurrence of DNA mutations, caused by smoking, solar UV rays or radioactive substances. To prevent two perfectly normal genes from generating a fusion RNA will require additional studies, to decipher the paths that lead to the fusion and their regulatory mechanisms.”

As the chimeric RNA is unevenly expressed by tumours, novel laboratory tests are required to reveal its presence. An assay has already been developed that can measure the levels of expression of this RNA in a few hours. Work is ongoing to determine if the expression of the hybrid RNA is linked to specific biological characteristics of the expressing tumours, e.g. their aggressiveness or resistance to therapies.

Professor Alberti points out: “These results open up the way for novel cures for cancer. The first, encouraging results have already been obtained. Inhibitory RNAs directed against the joining region selectively abolish the expression of the chimeric messenger RNA. Cancer cells expressing the chimera are killed by the treatment.” The scientists emphasize that even if these results are promising, several steps need to be taken before a viable new drug will be obtained. In particular, efficacy on large numbers of tumours in patients needs to be established, together with the potential toxicity of the novel cures.

Professor Alexander M.M. Eggermont, president of the European CanCer Organisation, commented: “Cancer is commonly considered to be a disease of the genome, whereby mutations of key genes, or oncogenes, induce activation and transformation. Professor Alberti’s findings show that mRNAs from perfectly normal genes, CYCLIN D1 and TROP2, can be fused together and lead to cell transformation and cancer.

“These findings reveal a novel mechanism of gene expression regulation, whereby the chimeric mRNA is unrestrained by the normal mechanisms that regulate RNA stability and activity.

“The chimeric mRNA is expressed in several tumours, and at higher levels in some of the commonest cancers such as stomach, colon, ovary, uterus and kidney.  This discovery is very promising as it provides new targets for treating cancer.”