Not only normal, but also cancerous stem cells were found in the liver
Many experts are of the opinion that up to 40% of liver cancer cases are caused by out-of-control stem cell division. However, despite all the efforts spent over the past few years, so far no one has been able to detect either normal or cancer stem cells in the liver.
Recently, Georgetown University scientists working under the direction of Dr. Lopa Mishra identified both types of cells for the first time. The results of comparing the genetic profiles of cancer and normal stem cells indicate that some experimental drugs designed to treat other types of cancer and currently undergoing trials can help in the fight against liver cancer.
According to preliminary results of experiments on mouse and human cell lines, an experimental drug – a stat3 protein inhibitor – effectively suppresses the division of liver cancer cells.
Hepatocellular carcinoma, or hepatic cell carcinoma, is one of the most common and intractable forms of liver cancer. The five-year survival rate after the diagnosis of this disease is less than 1%. The only effective treatment is surgical removal of the tumor, but this is possible only if it is detected at a very early stage. Unfortunately, in most cases, the diagnosed tumors are too large, and only complete removal of the organ and transplantation of the donor liver can help the patient, which is a very difficult task.
The authors have been studying the mechanisms of liver cancer formation for several decades. Previously, they found that transforming growth factor beta (TGF-beta) plays a key role in this process, since inactivation of the molecular mechanism controlled by it leads to the development of liver cancer in mice. Proteins belonging to the TGF-beta family contribute to the maintenance of the undifferentiated state of stem cells, and, if necessary, direct their differentiation. They are also powerful suppressors of tumor growth.
The results of later work showed that the loss of the ELF gene, active in stem cells and involved in the functioning of the TGF-beta-mediated molecular mechanism, is sufficient to induce hepatocyte malignancy. Currently, it has already been proven that ELF is inactive in the cells of more than 90% of malignant liver tumors.
These data suggest that uncontrolled dividing stem cells are the cause of the development of hepatic cell carcinoma. However, until now, this theory has not had convincing evidence, because liver stem cells have eluded scientists for a long time.
The direction of the search was suggested to the authors by transplant surgeon Lynt Johnson, who suggested analyzing the composition of the tissue of a recently transplanted donor liver. He suggested that stem cells of such an organ are especially active, because they need to restore a fully functioning organ. (The liver is the only organ of the human body capable of natural regeneration of significant fragments lost due to various reasons.)
The analysis of liver tissue of patients who underwent transplantation no more than 4 months before the biopsy brought long-awaited luck. According to the presented results, there are only 2-4 cells per 30-50 thousand hepatocytes of the regenerating liver, expressing in large numbers all known stem cell marker proteins, such as Stat3, Oct4, Nanog, ELF and the TGF-beta receptor.
According to the authors, these cells are very active, and in colored preparations they resemble stars due to the surrounding tags-antibodies specific to the listed markers.
In search of cancer stem cells, scientists treated liver tissue samples of 10 patients diagnosed with liver cancer with the same set of antibodies. The cells identified in this way expressed all markers of stem cells, except for receptors for TGF-beta, the absence of a restraining effect of which ensured their uncontrolled division.
After that, the authors used a mouse model of liver cancer to test what would happen if cancer stem cells stopped being stem cells. To do this, they created animals with a predisposition to liver cancer, but without the stat3 gene. Liver cancer developed in only 1 out of 40 of these animals, while in mice with the normal stat3 gene, the incidence of liver cancer was 70%.
Currently, the authors are testing the effectiveness of an experimental drug that blocks the activity of the stat3 protein in animals with a normal stat3 gene and an inactive TGF-beta-mediated mechanism. They expect to get positive results and claim that there are still a number of proteins selectively active in cancer stem cells and, thus, are potential therapeutic targets.
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of ScienceDaily
12.02.2008