Pharmacology

As tumors progress towards advanced stages they dedifferentiate, become more aggressive and lose the characteristics of the origin tissue. They also acquire the migratory capacity that allows the tumor to spread or metastasize to distant sites in the body; eventually causing patient death. For epithelial tumors, to metastasis the tumor cells undergo a process known as the epithelial-to-mesenchymal transition (EMT), which allows the cells to develop migratory ability.

Epithelial-to-mesenchymal transition

During EMT; cells also lose their proliferative capacity and become more stem-like. This remarkable transition leads to both increased invasiveness and an ability to evade numerous cancer treatments including hormonal therapies. In the present study the researchers find that EMT is aided by the synthesis of new ribosomes, which serve to synthesize the proteins require for cell functions.

Their study therefore argues that ribosome biogenesis may be more than just a pro-proliferative process. “Until recently, ribosomes have been consider to play only passive roles during the production of proteins. Our study shows that ribosomes potentially have complex, active roles and suggests that more attention  give to understanding how ribosomes contribute to cell physiology in health and disease states;” says Theresa Vincent, group leader at the Department of Immunology; Genetics and Pathology at Uppsala University, who has led the study together with Scott C. Blanchard at Weill Cornell Medicine, USA.

Synthesize the proteins

The researchers also demonstrated that by inhibiting the formation of new ribosomes, aggressive and hormone insensitive tumors could be partially reverted to a benign and non-metastatic type. “We used a small molecule called CX-5461 to inhibit ribosome biogenesis in mouse models of human tumors. We found that primary tumors reverted from an invasive type to a non-invasive type as well as potentially regaining sensitivity to hormonal therapy.

Importantly, CX-5461 treatment also resulted in a marked reduction of number lung metastases. This suggests that treatment with CX-5461 may enhance hormone therapy responsiveness in patients where this kind of treatment doesn’t work any more. We find this to be a remarkable breakthrough and we are currently pursuing a number of additional validation studies,” says Theresa Vincent.

Additional validation studies

Ribosomal protein synthesis in eukaryotes is a major metabolic activity. It occurs, like most protein synthesis, in the cytoplasm just outside the nucleus. Individual ribosomal proteins are synthesized and imported into the nucleus through nuclear pores. See nuclear import for more about the movement of the ribosomal proteins into the nucleus.
The rRNA is transcribe, at a high speed, in the nucleolus, which contains all 45S rRNA genes. The only exception is the 5S rRNA which is transcribe outside the nucleolus. After transcription, the rRNAs associate with the ribosomal proteins, forming the two types of ribosomal sub units (large and small). These will later assemble in the cytosol to make a functioning ribosome. See nuclear export for more about the movement of the ribosomal sub units out of the nucleus.