How to turn normal cells into cancer stem cells
It is believed that cancer stem cells underlie the formation of tumors, which makes them an attractive target for the development of new types of antitumor therapy. The study of these cells, however, is hampered by their small number, as well as difficulties with their isolation and cultivation in the laboratory.
The results of a new study by scientists from Stanford University (California) and the Weizmann Institute (Israel), published in the Cell Stem Cell issue dated 04/10/2008, indicate that the expression of genes in normal differentiated cells in a suppressed state is characteristic of embryonic stem cells and cells of various types of cancer. This discovery may be of great importance for the development of new anticancer drugs.
The ability to self-renew is one of the main properties of stem and malignant cells, but the existence of a universal gene program of "stemness" remains controversial.
Cancer stem cells were first identified in 1994 by scientists at the University of Toronto. In 2003, Dr. Michael Clarke, who was an employee of the University of Michigan at the time, first identified cancer stem cells in a solid tumor (breast cancer), and thus proved that the concept of cancer stem cells extends not only to oncological diseases of the blood. After that, Clark moved to Stanford University, which is currently a leader in research in the field of cancer stem cells. The university staff has already identified cancer stem cells in malignant tumors of the head and neck, colon, as well as in some diseases of the blood system.
One of the questions occupying the minds of scientists is the origin of cancer stem cells. In search of an answer to this question, the authors began to compare the genetic activity of embryonic stem cells with the genetic activity of normal adult stem cells. They found a large complex of genes active only in embryonic cells. The study of cancer stem cells showed that the profile of their gene activity is very similar to the previously identified profile of the gene activity of embryonic stem cells.
The researchers also found that the genes active in both types of cells are regulated by several common biological regulators. Moreover, with the help of one of them – the Myc gene – scientists managed to turn normal skin cells into cells with the properties of embryonic stem cells.
Activation of the Myc gene in normal cells, as well as two additional genes, Ras and I-kappa-B-alfa, led to the transformation of healthy cells into cells with all the signs of cancer stem cells. The final proof of their malignancy was that the introduction of such cells to mice caused the formation of tumors.
The authors have created a map of gene modules that helps to systematize the transcription programs of embryonic stem cells, normal adult cells and cancer cells.
Using the map, the researchers identified two predominant gene modules that provide differences between embryonic and adult stem cells. An interesting fact is that the transcription program, resembling the program of embryonic stem cells, is activated in cells of various types of human malignant tumors of epithelial origin and is a clear prognostic factor of metastasis and death of patients. The opposite model is typical for the gene module of adult stem cells: it is activated in normal tissues and suppressed in tumors.
Scientists have demonstrated that activation of c-Myc (but not other oncogenes) is sufficient to awaken in normal and tumor cells the gene program characteristic of embryonic stem cells. In the culture of primary cells transformed by the tumor-inducing Ras and IkBa genes, c-Myc increased the number of cells capable of forming tumors and possessing key properties of cancer stem cells, and also significantly increased the number of tumors forming in mice when these cells were injected.
This discovery indicates that upon activation of the transcription program characteristic of embryonic stem cells, adult differentiated cells can acquire the pathological ability to self-renew characteristic of cancer stem cells. The authors believe that the map of gene modules developed by them is a valuable tool for classifying and describing stem cells using expression profiles as a kind of "fingerprints" that will provide more reliable information than several molecular markers. In their future work, the authors hope to study in more detail the mechanisms by which these genes activate the transition of cells to a state of malignancy.
The authors believe that the ability to transform normal cells into cancer stem cells in laboratory conditions will greatly facilitate research in this direction. In addition, it turned out that cancer stem cells are much more similar to embryonic stem cells, capable of giving rise to all types of body tissues, than with more limited adult stem cells. This discovery will help researchers to understand in more detail the violation of the normal functioning of cells during their malignancy.
Portal "Eternal youth" www.vechnayamolodost.ru based on ScienceDaily: Cancer Stem Cells Created With New Technique and Module Map Links Embryonic Stem Cells And Cancer Stem Cells
11.04.2008