16 July 2015

The tumor can be re-educated

Researchers at Memorial Sloan-Kettering Cancer Center, working under the guidance of Dr. Scott Lowe, found that mutations of the APC tumor suppressor gene identified in more than 90% of colon cancer samples play an important role in the progression of the disease. In addition, they demonstrated the possibility of completely getting rid of the disease by restoring the activity of this gene.

Experts have long known that mutations that disrupt the normal activity of the APC gene can lead to the appearance of colon cancer. However, until now nothing was known about the role of such mutations in the later stages of the development of the disease. In experiments on mice, researchers not only found that mutations of this gene contribute to the progression of tumors, but also demonstrated that interventions restoring its normal activity can return cancer cells to normal and protect against relapses of the disease.

As part of their work, the authors created a genetically modified mouse model of rectal cancer. To do this, they used a technology known as RNA interference to inactivate the APC gene and induce the formation of rectal tumors.

In earlier models of the disease, the APC gene was irreversibly deleted, which made it possible to demonstrate the role of mutations inactivating it in the development of the disease, but deprived researchers of the opportunity to study the potential effects of restoring normal activity of this gene.

The new model obtained by RNA interference, on the contrary, makes it possible to completely restore the activity of the target gene. Restoring the activity of the APC gene in a mouse model of colon cancer for four days stopped the progression of tumors and normalized the work of the intestines of animals. Moreover, after a few weeks, complete regression of tumors was recorded in the animals, which did not recur during the next few months of follow-up.

According to the authors, the most surprising thing was that the restoration of normal activity of the APC gene transformed cancer cells and returned them to a visually normal state.

This was demonstrated by conducting additional experiments on intestinal organoids – tiny three-dimensional structures formed by cells isolated from the intestinal glands of mice. The internal structure of such organoids resembles the natural structure of intestinal tissue, which allows them to be used as a model for studying how genetic changes affect biologically aspects of colon cancer.

After exposure to APC-blocking RNA interference, the organoids lost their normal structure and acquired a spherical shape typical of cancer organoids. However, restoring the expression of the target gene resumed normal cell division and returned the organoids to their normal form.

Images of organoid cultures of intestinal cells obtained by immunofluorescence microscopy. In the spherical organoid pictured on the left, the APC gene was inactivated, which triggered a reaction similar to the development of cancer. In the organoid depicted on the right, which has the shape of a candy wrapped in a wrapper, the activity of this gene was restored, which ensured the normalization of the process of cell division and development.

The APC gene regulates the WNT protein-mediated signaling mechanism, which is inactivated in the cells of most colon tumors. The data obtained indicate the possibility of developing a new class of drugs that reactivate this signaling mechanism in malignant cells.

Such drugs can be effective against a wide range of tumors whose cells have mutations of the APC gene. Moreover, experiments on mice have shown that restoring the expression of this gene is also effective against tumors with additional mutations, such as mutations of the Kras and p53 genes, identified in about half of human colon tumor tissue samples. In the figure from the article in Cell, actively dividing stem and progenitor cells are highlighted in yellow, differentiated into intestinal epithelial cells in blue: secretory (Goblet cells) and suction (enterocytes).However, the authors note that it may take many years to develop a new class of drugs and evaluate their long-term clinical efficacy.

Earlier studies have shown that complete blocking of the activity of the WNT-mediated signaling mechanism can have a very serious toxic effect on normal intestinal cells and lead to severe side effects. Therefore, only small molecules that carefully modulate the operation of this mechanism can be suitable for clinical use.Article by Dow et al.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on EurekAlert materials!:
A single gene turns colorectal cancer cells back into normal tissue in mice.  

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