Colon carcinoma: Smothered in waste

20. June 2012
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If the cellular garbage disposal system does not operate properly, cancer may arise. Using tailor-made siRNAs, researchers at the University of Erlangen were able to virtually smother colon tumours into waste material, without affecting healthy tissue.

“You have intestinal cancer!” Some 65,000 people in Germany were confronted with this diagnosis in 2008, according to data from the Robert Koch Institute. After breast and prostate cancers, cancers of the gastrointestinal tract are the second most common cancer in incidence and also the second leading cause of cancer death in Germany. Colorectal cancers make up the lion’s share of all intestinal cancers.

APC: rubbish removal for β-catenin

In most colon tumors, a gene called Adenomatous Polyposis Coli (APC) has mutated. APC is present in all vertebrates and encodes a tumour suppressor. APC protein plays an important role in a specific signaling pathway called Wnt: normally, the APC protein is a component of a cellular waste disposal complex which breaks down the protein β-catenin. As almost always in biochemical processes, things then get a bit complicated. A very important function of β-catenin is signal transmission in the Wnt pathway. In the process it (??) is transported into the nucleus and helps a transcription factor there in the reading of additional genes. If mutations turn up in the APC gene, the β-catenin disposal complex is defective. β-catenin cannot be broken down sufficiently, and it floods the cell nucleus. The countless β-catenin molecules then bind to other proteins – with fatal consequences: the cells divide uncontrollably, cancer cells are created.

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The dosage has to be right

The mutations in the APC gene however do not result in a catastrophic failure of the APC protein, but only in truncated APC proteins that possess some β-catenin-binding sites. These shortened APC proteins are present in virtually all colon tumours. “It is amazing that the tumor does not simply dispose of the entire APC protein. Apparently it needs a “remnant-inhibition” of β-catenin in order to grow further,” explains Prof. Dr. Jürgen Behrens of the Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen, why completely unfettered β-catenin would virtually mean the suicide of a colon tumour. Scientists do not yet know the reasons for this. “Both too many of the truncated APC protein and too few of them are bad for tumour growth. We have taken advantage of the latter,” says Prof. Behrens. Together with his team, he was able to curb the growth of colon cancer cells in mice by using specific siRNAs (si standing for small interfering) against the truncated APC gene. Chemotherapy can do this too, one might think. This is true, but the highly specific siRNAs only stop the growth of cancer cells without affecting healthy APC proteins.

siRNAs hold great potential

The U.S. scientists Andrew Z. Fire and Craig C. Mello published some 14 years ago the mechanism of RNA interference, which they had studied in the nematode C. elegans. In 2006 they received the Nobel Prize in Medicine for this. RNA interference is a naturally occurring mechanism of gene silencing. This involves the major cell double-stranded RNA (dsRNA) getting cut in the cell into short double-stranded RNA fragments with the help of certain enzymes. Subsequently, these fragments split into single strands, the so-called siRNAs. Embedded in an enzyme complex, the siRNA then activates the surrounding enzymes to cleave mRNA which in its base sequence is complementary to the sequence of the siRNA. siRNAs thus prevents translation of a gene into a protein. Targeted steering of this translation has great pharmacological potential, because the mechanism of RNA interference works in almost all eukaryotes and appears to be a highly conserved process. Returning to the topic of colon cancer: “Theoretically, one could specify the individual mutation in the APC gene for patients with colorectal cancer, and produce customised siRNAs”, says Prof. Behrens. Scientists have already succeeded with this in in-vitro and in naked mouse model. “Transfering these attempts to human colon cancer patients however is not easy. Transporting chemically synthesised siRNAs in-vivo efficiently to the organ concerned is pharmacologically challenging”, he adds.

However, waiting for the big breakthrough in personalised medicine which involves RNA interference is not the aim of Prof. Behrens group. “What is crucial in our work is that we can also stop tumour growth by stimulating the overproduction of β-catenin, rather than block it out completely”, says Prof. Behrens. “Whether that is possible with RNA interference though is uncertain. Yet is is a new pharmacological approach to slow, or even stop, tumour growth in colon cancer”.

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Medicine, Oncology

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nico cok
nico cok

what is the connection with Dan Burke’s ideas about salvestrols?
nico cok
health practitioner

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