[seminar Series] Anti - Cancer strategy for glioblastoma multiforme by targeting cancer stem cells

1. Hello my name is oh, nuri. . I’m doing a Ph degree in biomaterial engineering laboratory of bio and brain engineering department. Today, I’d like to introduce more in detail based on last lecture about stem cell in cancer biology. 2. I’m going to give you an overview of glioblastoma and a function of cancer stem cell related to glioblastoma on the basis of professor kang’s lecture and then explain why mesenchymal stem cell and heterogeneity are important in this lecture. 3. Unfortunately, there are no treatments for glioblastoma now with current medical technologies. Some people who have brain tumor could survive for a long time. In particular, we have to know about WHO grade of glioblastoma to judge how serious it is. 4. Then, what is WHO grade? It means a criteria which divides of the types of cancer under severity with a microscope. It is hard to tell that this is cancer if Brain tumor belongs to WHO grade 1 and 2 whereas brain tumor belongs to WHO grade 3 and 4 could be considered as cancer and begin to treat. In here, what to decide the grade of brain tumor is just observe an area where can generate cancer and decide the grade seeing differences of morphology. If we want to study about differences of treatment efficiency among various cancers, we have to know about WHO grade of cancer to compare differences at the same grade. 5. Brain tumor, glioblastoma, originates from astrocyte which is one of the glia cells and glioblastoma is the most common and aggressive malignant primary brain tumor in human bodies. Glioma has different severity depending on their grade. If some people were diagnosed with grade 2 brain tumor, 50% of people of them live for over 5 years whereas some people were diagnosed with grade 4 brain tumor, their mean survival is just 15 months. Thus, this lecture focuses on glioblastoma which is WHO grade 4 brain tumor. 6. The paper published in 2005 showed that combination therapy of radiation and chemotherapy is the best treatment for glioblastoma, and the therapy can extend survival rate for just 2 months more. Some reports show that 5% people of them who have glioblastoma can live for 10 years, and anyone doesn’t know why they live for a long time. At this moment, i’ll give you some clues from now on. 7. I am going to help you to understand about this topic. I’ll explain what stem cell is before introducing cancer stem cell. Firstly, spem cell fused with ovum which eventually leads to the development of an embryo. As embryo begins to cell division, and it can form blastocyst. Blastocyst consists of trophoblast, blastocyst cavity, and inner cell mass. In other words, individual inner cells indicate embryonic stem cell which is undifferentiated cells that can differentiate into specialized cells and divide to produce of more stem cells. The most important properties of stem cell can be represented to self-renewal and pluripotent, whereas adult stem cells are also undifferentiated cells and found throughout the body after development. They have two properties such as self-renewal like embryonic stem cells and multipotency. 8. What is the cancer stem cell? The cells which have properties of stem cell was isolated in cancer tissue. The cells can replicate themselves and differentiate into different cell type. Their characteristics are very similar to stem cell. However, the most important characteristics of cancer stem cell are tumorogenic potential, which means cancer stem can make cancer tissue. Some properties of cancer stem cell show similarity like stem cell. Researchers cannot be sure of the presence of cancer, however. The presence of cancer stem cell firstly was found in leukemia but the main difference between leukemia and solid tumor is that in leukemia each cell indicated cancer whereas in solid tumors each cell is not important because various cells including cancerous cell, macrophage, and stroma cells are related to form cancer tissue or organ. Leukemia can be explained at single cell level, whereas it is not the case for the solid tumor. For this reason, it is doubtful that the stem cell concept found in leukemia can be applied directly to solid tumor. But some paper showed that stem like cells are isolated in glioma, therefore, concept of cancer stem cell may be applied to cancer. 9. The main difference of stem cells isolated in leukemia or glioblastoma is marker on surface of cancer cell because leukemia have specific marker on their surface whereas solid tumor doesn’t have any specific marker on their surface. So, it is doubtful to explain of the presence of cancer stem cell in gliobalstoma. some paper showed that stem cell isolated in glioblastoma can be found, however. To confirm stem cell existence, stem like cells isolated in glioblastoma are cultured in cell culture dish. If the cell isolated in glioblastoma is right, the cells can be attached on dish in standard culture condition and morphology of the cell in culture condition can be formed like stem cell. After checking their properties, the stem cell markers of the cell were analyzed, however, their morphology like stem cell doesn’t perfectly match molecular analysis to identify stem cell marker, so, if the cancer stem like cell can attach on dish and differentiate to original cell at the same lineage. We can decide potentially that the cell may be cancer stem cell. 10. Cancer tissue can be made when cancer cells were injected into subcutaneous tissue for in vivo test. The shape of the cancer tissue was formed by cancer cells looks like beautiful round shape, but this shape is not real. If we injected cancer stem cell into the suitable tissue, the shape is real, there are no boundary line. If we want to get the highest efficiency of drug to treat the cancer, we have to use cancer stem cell to make cancer tissue in suitable tissue not subcutaneous tissue. 11. To definite the properties of cancer stem cell, international society for cellular therapy position statement made minimum requirement. So, we can identify properties of mesenchymal stem cell based on international society for cellular therapy position statement because Mesenchymal stem cell is the most important candidate in glioblastoma. First, mesenchymal stem cell can be attached on cell culture dish. Second, mesenchymal stem cell have to show positive result of CD105, CD73 and CD90 protein whereas mesenchymal stem cell have to show negative result of CD45, CD34, and CD13 protein. Last, mesenchymal stem cell have to differentiate into osteoblast, adipocyte, and chondroblast under certain culture conditions. If we want to classify mesenchymal stem cell from other cells, the cells isolated from cancer tissue meet the three conditions. In particular, criteria number 1 and 3 is the most important to decide whether stem cell or not because criteria number 2, phenotype, is flexible. 12. Why is mesenchymal stem cell important in this lecture? Glioblastoma is originated from neuroepithelial cells. Neuroepithelial cells are originated from ectoderm whereas mesenchymal stem cell is derived from mesoderm. What is the common part between glioblastoma and mesenchymal stem cell? Some papers showed that protein expression of glioblastoma is very similar to pattern of protein expression of mesenchymal stem cell. The result indicated that relationship between glioblastoma and mesenchymal stem cell is very close through analysis of molecular level. Besides, another report showed that glioblastoma which has similarity with mesenchymal stem cell is the most aggressive brain tumor. So, mesenchymal stem cell becomes more important and we can develop new treatment method based on this analysis. 13. In this slide, I’ll give you some information about heterogeneity. We generally think that heterogeneity means cancers with various sites have different cancer stem cell , however, heterogeneity is a little bit different in this lecture. Heterogeneity means that different site of cancer have different cancer stem cell at the same cancer. Therefore, heterogeneity is the most important concept in this lecture. If you want to analyze stem cell in cancer, we need to get cancer tissue at the same site. To analyze more accurately, we can stain glioblastoma using 5-ALA dye. After staining, glioblastoma can be seen as red color whereas normal tissue can be seen as blue color. Finally, we can get the cancer tissue at the same site. 14. The properties of this dye cannot penetrate brain blood barrier, but if brain blood barrier is broken, the dye can be penetrated inside the brain and then it can stain glioblastoma. Consequentially, protoporphyrin IX produced by 5-ALA begins to accumulate inside glioblastoma. Brightness of the dye is different with other sites. That means the properties of cancer is different with other sites and if surgeon performs the surgery to remove a wide range of tumor, patient may live for a long time. 15. If some sites which have no tumor might be removed by surgery after identifying the site is origin of tumor, the survival rate of the patient may increase. In this slide, I’ll give you some information about the process to search where tumor's origin is. Neuron stem cell is located in subventricular zone. So, there are two hypotheses about generation of tumor. One thing is that normal stem cell becomes cancer stem cell which can generate tumor, glioblastoma. Another thing is that normal brain cells become cancer cells, one of the cancer cells becomes a cancer stem cell. Which one is the correct answer? I think that two hypotheses may be related to generation of tumor. And if cancer stem cell is the most important to generate tumor, we have to remove the subventricular zone which has the highest possibility to generate tumor. 16. The three groups can be suggested to search the origin of tumor. One group is 5-ala positive subventricular zone; another group is 5-ala negative subventricular zone or 5-ala negative cortex, the other group is 5-ala positive tumor through molecular analysis, we can find origin of tumor. 17. Some paper showed that if researchers can remove the site (subventricular zone) assumed to have cancer, they got the result that effect of treatment is increase. Through professor kang’s lecture, we understood that glioblastoma is the most aggressive tumor in the brain and there is no way to treat glioblastoma perfectly. I appreciate to prof. kang to make us understand glioblastoma very well. Thank you.