Introduction to Cell Transformation:
The process of eukaryotic cells turning to cancerous cells from the normal cells is known as cell transformation. In cancer cell transformation there are few different modifications. In basic, there is a balance between cell growth and cell death. There are several pathways in the body that dictate the cell to grow and cell to die. So, converting a normal cell into a cancerous cell, the growth pathway inside the cell should be upregulated and the death pathway in the cell should be downregulated.
The major cause for turning normal cells into cancerous cells is the modification of how they make proteins. Different types of protein that are required for the cell to grow as well as required for the cell to die. The protein that helps the cell to grow is mostly made up of genes known as protooncogenes.
The gain of function mutation is that genes will produce more and more of those growth factors and all the protein that help the cell to grow. There are other proteins that regulate the growth and that ultimately dictate the cell to die by apoptosis. The second type of gene is known as tumor suppressor gene because the product of those gene suppresses the growth of the tumor. So, loss of function mutation of these tumor suppressor genes also pushes the cell from normal to cancerous cell.
Balance Between Cell Growth and Cell Death:
There is a balance between a gene and the modification of such genes either by gain of function or loss of function are mediated in those genes.
Changes in those different gene that lead to the production of different types of protein or that alter the protein production is known as mutation. So, there are mutation such as the oncogene and tumor suppressor gene that turn cell behavior from normal to the cancerous cell.
Types of Mutations in Cancer Cell Transformation:
Generally, there are two types of mutation based on the trend of mutation i.e., point mutation and chromosomal mutation. Both of these can turn normal cells into cancerous cells.
Point Mutations
(Role of p53 Tumor Suppressor Gene
Ras Protein and MAPK Pathway Activation)
It is the change in the single nucleotide of a gene. E.g., P53 tumor suppressor gene. If there is a mutation in the p53 gene, it makes it inactive. As, p53 is very important in regulating cell cycle, and also induce programmed cell death or apoptosis. As p53 will be inactive, the apoptosis pathway will be blocked and the regulation of cell growth will also be prevented. As a result, it will transfer normal cells into the cancerous cells.
Another type of protein is Ras protein. Ras is a signaling molecule required for the processing of MAPK (mitogen-activated protein kinase) pathway that ultimately produces a lot of growth-related protein, i.e., the protein required for cell cycle to progress from one phase to the next phase of cell cycle. So, if Ras remains active or gain function mutation, it gets hyper active. As Ras will keep the signaling process on, the negative regulation of RAS will be difficult to achieve. So, RAS keeps on producing all those different cyclin and protein that will be required for the cell cycle to progress. So, the cell cycle will continue, cells will start growing continuously and produce a lot of cells and produce tumors.
In most of the cases, multiple mutations are required that are gathered together which convert a normal cell into a cancerous cell. So, one single mutation is unlikely enough to cause cancer.
Both of this mutation continues, a gain of function of Ras and loss of function of P53 along with both will give signals of higher growth and less death that can ultimately suggest to grow and not to die i.e., that can trigger that change and convert a normal cell into a cancer cell.
Chromosomal Structural Mutations and Cancer
There are three types of structural alteration that can take place
- Deletion from the chromosome
- Translocation of one fragments of the chromosome to another chromosome
- Insertion of some other genetic element somewhere between specific genes inside the chromosome.
- Either of three modifications can also lead to different expressions of the protein that can lead to cancer.
Deletion
(Retinoblastoma and Cell Cycle Regulation)
Retinoblastoma, predominately in children at the early age. In this case, in chromosome 13, there is a specific point in the long arm with a specific sequence which gets deleted. Deletion of a specific segment of the long arm of chromosome 13 caused the process of the regulation of cell cycle to fail. As a result, cell cycles progress and progress uncontrollably and can turn into cancerous cells. Retinoblastoma proteins have a very important role in controlling progression of cell from G1 to S phase of cell cycle. Because, retinoblastoma protein inactivates th transcription factor (E2F) that will be required for the production of the growth factor protein that will progress the cell from G1 to S phase of cell cycle.
Translocation
(Burkitt Lymphoma and Myc Overexpression)
Burkitt lymphoma is a rare, fast-growing, aggressive type of B-cell non-Hodgkin lymphoma (NHL) that often affects children and young adults. In this case, a fragment of chromosome 8 is translocated and passes to the bottom and the telomere part of chromosome 14. So, the arm of chromosome 8 will shorten while the long arm of chromosome 14 gets longer. Because the segment of chromosome 8 that would translocate certain gene sequences for producing myc. Myc is a transcription factor that is required for the production of almost 50% of the growth factors/proteins/hormones that our body produces. If the Myc activity is upregulated, it can turn a cell into a cancerous cell. Normally, in chromosome 8, the Myc is located in a properly tightly highly controlled fashion for the production of protein. But, once it is transferred to chromosome 14, it would be located nearby immunoglobulin heavy (IgH) chain proteins. So, this IgH protein is produced constitutively throughout the body. So, this Myc is next to the IgH segment of the gene. So, in this case, Myc production is uplifted because of the gain of function of the Myc production. As a result, it turns normal to a cancerous cell and caused Burkitt lymphoma.
Insertion
(Virus-Mediated Cancer and Myc Regulation Disruption)
This is the third gene inserted between two other genes. Some cases of virus mediated cancer AVL (Armed oncolytic vaccinia virus).
There are three different types of exons that ultimately produce Myc protein. After splicing and post transcriptional modification, RNA processing. Normally, exon 1 code for the region of Myc which is regulatable, so regulatory region of c-Myc. While exon 2 and 3 produce activators of Myc protein. Normally, once all of these exons after splicing mature RNA is produced, ultimately fully functional Myc is produced which has two protein domain activator and regulator. So, the expression of protein and also the activity of the Myc by binding will be controlled. So, once Myc is not needed, in such cases the inhibitor binds to the regulatory region of the Myc, preventing the Myc to be expressed and do its activity.
But, when the AVL virus infects the human body, AVL inserts its own genetic element in between the exon 1 and exon 2. And that changes the way splicing occurs. So, it produces Myc protein that lacks the regulatory subunit. In this case, Myc protein only has an activatory unit and now it is uncontrollable and it will be active all the time inside the cell. So, it will tell all the pathways inside the cell to be turned on. And, as it is a transcription factor for many growth factors and protein inside the body. So, these growth factors keep on producing inside the cell. As a result a cell can turn into a cancer cell. This is also an example of virus induced transformation of a normal cell into a cancer cell.