May 24, 2022

Today’s topic is neoplasia part two. Today we will discuss the molecular basis of cancer briefly. Now to understand the molecular basis of cancer, I have divided today’s article into three sections.

  1. we will discuss some fundamental principles briefly, and we will talk about non-lethal mutation, monoclonality and the target of cancer.
  2. What are the essential alterations needed to transform a normal cell into a cancer cell or malignant cell?
  3. We will draw a simplified flowchart to show you a simplified overview of the molecular basis of cancer

1. The fundamental principles.

If you ask me, what lies at the heart of carcinogenesis from a molecular point of view, or, what is the most important thing that is responsible for the development of cancer? I have to say that non-lethal mutation lies at the heart of carcinogenesis.

I know it sounds like a really fancy term, but don’t worry, let me explain what I mean by non-lethal mutation. To understand non-lethal mutation, first, we have to know what mutation.

To understand mutation, first, we have to know what is a gene and to explain that thing I have drawn a simple image as you can see, this is a cell A cell has a cytoplasm and nucleus now inside the cytoplasm there should have been a lot of organic please, but I did not draw those organically because we are talking about the nucleus now. So in a cell we will have cytoplasm nucleus in the cytoplasm different organelles and in the nucleus, we will have chromosome right and as you can see, I have zoomed into one chromosome and I have drawn it here okay. So, this is a zoomed in version of say for example, this chromosome and inside every chromosome, we have the helical structure named DNA. So, you can see we have DNA here, we have DNA here and inside these dnase we have gene. So, gene is a part of DNA and gene is also known as the unit of heredity. genes can be classically defined as a unit of DNA that can encode a particular protein or RNA molecule. Now, since nowadays, we have discovered a lot of information regarding the way genes are expressed, so much more complicated definition of gene are available, but let’s not go into those biochemists to definition because otherwise, the video will become extremely long. So that is Gene you need a DNA that can encode a particular protein or RNA molecule. Now what is mutation? mutation means permanent, heritable change in the DNA base sequence of an organism. Permanent heritable. Change in the base sequence of DNA of an organism. Now, if we alter the base sequence of DNA, will that alter the gene, of course, the gene will get altered. So, mutation we can say in other words, it is also altering the gene. And now that we have understood, what is gene, what is mutation, now we can go back to the first point that was non lethal mutation. Non lethal mutation means in this type of mutation, there is permanent heritable change in the DNA sequence. However, the cell did not die. Now, is that a good thing or a bad thing? If we think from the point of view of a cancer? Well, if the mutation was lethal, the cell would have died, and in the cell died, there was absolutely no way cancer could have developed. So, in a sense, if the cell had died, that would have been a good thing from the point of view of cancer, that cell died, so there is no cancer. Now, what will happen if there was a non lethal mutation, but the result of mutation was neutral, nothing will happen no tumour will be formed. So when does non lethal mutation resulting carcinogenesis This is very important, dear viewers, non lethal mutation will result in carcinogenesis when that mutation will alter the proto oncogene or the tumour suppressor gene, okay. So, we will discuss about those genes after a while. So, just remember that non lethal mutation when altering those potent oncogene or tumour suppressor gene can result in cancer formation in the long run. So, now that we have discussed the first fundamental principle that we need to know to understand the molecular basis of cancer, now, we will move on to the next fundamental principle and that is monoclonal ality Always remember that tumour are in fact most of the tumours are monoclonal a tumour is formed from clonal expansion of a single precursor cell that had encountered a non lethal mutation. Now to understand monoclonal ality further, first, I will give you the example of X chromosome inactivation that occurs named female. And to understand the X chromosome inactivation, you can see that I have drawn another image here. So this is the mother. Notice that she has two X chromosomes and we have labelled those X chromosomes as x a, this is the father notice, the father has one X chromosome and one Y chromosome, and we have labelled the X chromosome as x B. Now, this is the daughter, notice that she has one X chromosome from the mother and one X chromosome from the Father. Now, what will happen to this daughter in the blastocyst stage of development recall that in the blastocyst stage, there is random inactivation of the X chromosome.

So, in some cells of the blastocyst, the x A will be inactivated and in other cells of the blastocyst the x B will be inactivated and always remember these inactivation is irreversible. So, once inactivated, in all the daughter cells, that configuration will remain intact. Say for example, we are talking about this particular cell. Okay, and supposing this cell during blastocyst stage of development, the X chromosome that came from the Father that means the x b got inactivated the X chromosome that came from the mother that is the x a, that remained active and since this configuration is irreversible, so in all the doctor cells that has derived from this sale, that configuration will be intact. So, in all these DRS cells, you can see that the B is inactivated in all of them and a is kept active. And we can use this thing to diagnose criminality of a tumour. Now, let us suppose that this particular cell encountered a non lethal mutation, and now it is producing tumour. So, all the cells that have derived from this particular cell will carry that non lethal mutation. And at the same time, they will carry that same configuration of X chromosome inactivation. And in case of female we can use these two SS mano criminality. That is we can use polymorphic x linked marker to assess mono criminality in female these markers include glucose six phosphate dehydrogenase, there is also another enzyme known as Iran a to sulfatase another enzyme known as phosphoglycerate kinase, all these can be used as polymorphic x linked marker to detect model clonality in females. Similarly, in some cancers where there is translocation, say for example, in chronic myeloid leukaemia, that translocation can be used to assess monoclonal ality similarly in some other tumours, say for example, B cell lymphoma and T cell lymphoma, we can use immunoglobulin receptor and T cell receptor rearrangement to detect monoclonal ality of B cell lymphoma and T cell lymphoma respectively. Okay, so that is briefly about mono criminality. So now, we will move on to the last fundamental principle that we need to understand the molecular basis of cancer. And that is a discussion about targets of cancer. So there are four classes of regulatory genes that are the principal target of genetic damage. When these genes are mutated, there is chance of development of cancer in the long run. So what are these genes? As you can see, these genes are protooncogene tumour suppressor gene, genes that regulate a ketosis, and genes that regulate DNA repair. So let’s talk about these genes briefly. So what is proto oncogene proto oncogene is the normal gene that is found inside ourselves, its function is to encode proteins that regulate cell proliferation, and cell differentiation. It also has some role in signal transduction. And it also has some mitogenic effect that is it can trigger mitosis and cell cycle. So we can see that we need proto oncogene for the normal growth and differentiation of ourselves. When the proto oncogene gets mutated. We call that oncogene. Okay. And one interesting thing I would like to add, in fact, oncogene was discovered first, and then the scientists realised that what they have discovered is actually a mutated form of a normal gene. That’s function was to help cellular growth and differentiation. But when that protooncogene gets mutated, it becomes oncogene and oncogene can result in cancer development in the long run. So, examples of proto oncogene include NYC gene, W NT gene, etc. On the other hand, tumour suppressor gene are the opposite of oncogene tumour suppressor gene inhibit cell proliferation, and they also inhibit tumour development. Okay, so that is tumour suppressor gene. And one thing that I would also like to add here, when there is mutation in the proto oncogene the mutation is of dominant type, and my dominant I mean, if one of the any of the proto oncogene is normal, The other alien got mutated, the cell will transform despite of the presence of the normal alley, okay? So that is about protooncogene. And in case of the tumour suppressor gene, both alley must be mutated, okay, for the tumour suppressor gene to have diminished function. Okay, so there is an important difference between proto oncogene and tumour suppressor gene. Now, the best analogy to understand protooncogene oncogene and tumour suppressor gene is to use the analogy of a speeding car. So suppose you’re in the highway, it’s a holiday, so the roads are empty, so you want to speed up. So what do you do, you just flowed the gas pedal. So now your car is increasing in speed. And that is like the function of proto oncogene when our cells decide to grow rapidly, it will use those protooncogene to proliferate.

Now after it, after a certain time, you realise that you have gained a high speed in your vehicle. So now you want to slow down. So what do you do, you just remove your foot from the gas pedal, right? And then the car normally slows down. But what will happen if even after removal of your foot from the gas pedal, the car doesn’t slow down, that is what will happen if your gas pedal is stuck. Okay, so that is the function of oncogene. So always remember oncogene is like a stacked gas pedal. So how will you slow your car now, your gas pedal is now stuck. So the only way you can slow your car is by using the brakes. Now what will happen if your brakes are now also defective, and the brakes are like the tumour suppressor gene, okay. So think of that analogy. And when your accelerator is stuck, and your brakes are defective, and you are driving very fast, the end result or the outcome is not good, either you will crash or you will have a serious injury. And similarly here, when we have mutation in the proto oncogene, which has now become an oncogene, and when we have mutation in the tumour suppressor gene that can result in formation of cancer in the long run. The other two regulatory genes that are also target of genetic damage are genes regulating apoptosis, and genes regulating DNA repair. Now, I have a separate video about a potosi’s. But to say in short, a potosi’s is a pathway of programmed cell death, where the cells are committing suicide and a potosi’s is a better alternate, a better alternative, when the cells are so much damaged, that their DNA cannot be repaired. Because if we keep those cells with those severely damaged DNA alive, then there is risk of mutation in those DNA and that can result in development of cancer in the long run, okay. So, in the cells that have either been induced by radiation cytotoxic drug or some viral infection, or due to some other cause, and the DNA has been damaged beyond repair, in those cases, killing those cells are able to seize may be considered a better alternative. So, when the genes regulating April toeses, are mutated, a pitocin will not occur, and then those cells will not die, and there will be increased chance of development of cancer. Now, genes that regulate DNA repair, those genes are also another target for genetic damage. And if there is damage to those genes, that will also result in cancer formation indirectly. Let me explain. Now, if we damage the genes, which regulate DNA repair, what will happen that will result in a decrease in the DNA repair. So now protooncogene tumour suppressor gene, when those genes are getting damaged, they won’t get repaired

and As a result of lack of repair of the proto oncogene and tumour suppressor gene, it will cause development of cancer in the long run. So, now that we have discussed briefly the four target genes for genetic damage, now, we will move on to the second section of today’s video, where we will briefly discuss the essential alterations that are needed for malignant transformation. So, in your textbook, you will see that there is seven essential alterations that are needed for a normal cell to become malignant cell or that is needed for malignant transformation. The first one is called self sufficiency in gross signal. And this is mainly done by the oncogene remember the analogy I said earlier, oncogene is like a stuck gas pedal, what happens to your car when your gas pedal is stuck, your car will accelerate even after you have removed your feet removed your foot from the accelerator. Similarly, in order for a cancer to develop, there has to be self sufficiency in the growth signal that is the cell must be able to grow even after the absence of the stimuli, okay. So, that was the first point. The second point is in sensitivity to inhibitory growth signal. That means tumour cells are insensitive to inhibitory growth signal or growth inhibitory signals that causes inhibition of cell proliferation in normal cells, say for example, transforming growth factor beta, also known as TGF beta, this is a inhibitory signal, this inhibits growth of normal cell However, this won’t affect growth of tumour cells and that is when those cells will become cancerous cells in the long run, okay. So, that was the second essential alteration for malignant transformation that is insensitive to growth inhibitory signal. The third essential alteration is evasion of a potosi’s or escape from a potosi’s and we have already discussed about that the fourth essential alteration for malignant transformation is impaired DNA repair. And we have also talked about that the fifth point the fifth essential alteration for malignant transformation is unlimited replicated capability. When incel gives unlimited replicated capability, that can become malignant cell in the long run, and how does that happen? That happens by maintenance of the land and function of telomere. Now, what is the telomere? You may be asking? And this is a very interesting thing. So I am writing here, telomere. Now, telomere is just repetitive sequence of nucleotides. They are found at the ends of chromosomes. So if I draw a chromosome here, inside the chromosomes, we have the DNA, right? So I’m drawing these helical DNA and at the ends of the chromatid. These are the sites where we will have telomere. Now what is the function of telomere normally, we’ll always remember that when a cell is dividing, chromosomes are replicating and during every chromosomal replication, there is loss of chromosomal material, and that loss usually occurs in the ends of the chromosome. And since telomere is at that location. So in fact, with every chromosomal replication there is loss of nucleotide from the telomere But those are not important genetic material, those are just repeated the nucleotide sequence. So, that is not hampering the genetic content okay. But what is happening with every cell division the telomere is getting shrinked Okay. So, there will be a time after Say for example, a lot of cycles of cell division that the telomere will become absent and that is the time when if there is further cell division, the genetic material will begin to get lost and ultimately, there will be truncation. Okay, so, in case of melanin tumour, what do they do? They use different mechanisms to maintain the telomere. So, if you can maintain the telomere, even when we are dividing, the telomere is not shrinking, what will happen that will make those cells immortal. That is the reason why, in a lot of your textbooks, you will see that cancer cells are immortal cells, because they have figured out a way to maintain the function and lengthen the telomere okay. So, that was the fifth essential alteration that is needed to transform a normal cell into malignant cell that is unlimited replicative capability or in other words, the ability to maintain the length and function of the telomere. The sixth essential alteration for malignant transformation is sustained angiogenesis. Recall that angiogenesis means formation of new blood vessel. And the thing is, cancer cells are malignant cells, they also need nutrients and in order to get nutrients, they need blood supply, okay? And in order to get blood supply, what do they do? They induce angiogenesis, by different factors. One of the important factors that they use is known as vascular endothelial growth factor on the E, G, F, okay. And there are other factors that are released from the mending themselves to induce angiogenesis. The last essential alteration for malignant transformation is the ability of the cell to invade and metastasis. And I have discussed about invasion and metastasis in my previous video. So, now that we have discussed about the essential alterations that are needed for many men transformation, now, we will move on to the last section of today’s video. And now, I will show you a flowchart to give you an overall idea about the molecular basis of cancer. So, you can see that I have drawn a flowchart depicting a simplified scheme about the molecular basis of cancer. So, let’s go through the flowchart. So, we will begin from here, you can see that this is a normal cell and the normal cell was exposed to some DNA damaging agent Say for example, Southern chemical salting virus and certain radiation. Now, what did they do? Those DNA damaging agents can damage the DNA of that normal cell. Now, sometimes the damage is not severe in those cases, the DNA can be repaired, and in that case, the cell will return to normal. Okay, so DNA got damaged, but then DNA again, repaired and now it became normal again. But what will happen in the DNA is not repaired whenever there is failure of DNA repair, that will result in mutation of the genome. And one thing you can see that the mutation or failure of the DNA repair can also happen due to some inherited defect in the regulatory gene that used to repair DNA or that used to do a ptosis. So we also see an inherited mutation here. can also result in failure of the DNA repair. So, what will happen? Whenever there is failure of the DNA repair, there will be mutation of the genome. And as we have said previously, then there will be mutation in the proto oncogene that will transform into oncogene there will be mutation in the tumour suppressor gene, and also mutation in the genes that used to regulate a ptosis. So, whenever there is mutation in the tumours suppressor gene, and mutation in the proto oncogene and as a result formation of oncogene, these two things will result in unregulated proliferation of the cell okay. So, as you can see unregulated proliferation of the cell at the same time, since we cannot kill those cells via a potosi’s, so, that will also result in unrelated proliferation of the cell. Then what will happen, there will be clonal expansion as we have said before, that tumour is monoclonal So, there will be clonal expansion of the cell and as we know, tumour needs blood vessels, so, there will be angiogenesis, and also, the tumour cells will try to evade our immune system. So, the tumour cells that are antigenic, they may die and the tumour cells that are less antigenic, they will survive, okay. And now comes the interesting part and that is tumour progression, it is seen that with time, the aggressiveness of the tumour increases and so does the malignant potential. And it is seen that this increase in their aggressiveness and in their malignant potential is not only due to increase in the number. The thing is, although we say that tumour is monoclonal, however, as the tumour is progressing, multiple mutation occurs in those neoplastic cells. tumour progression most likely results from multiple mutation that will occur in the tumour cells independently, and those multiple additional mutations will create sub clones of tumour cells with varying ability to grow, to invade to metastasis, and to evade therapy. And also remember during tumour progression, there will be immune as well as non immune selection of those clones, say, for example, that sub clone of the tumour that are highly antigenic, they will get destroyed the sub clone of the tumour that are less antigenic, they will be positively selected. Similarly, the sub clones of tumour that require less growth factor, they will be positively selected. Okay. So, this is In short, the explanation of the molecular basis of cancer. Now, molecular basis of cancer is a very big topic, and I tried to make a brief video about this or that you don’t you do not get overwhelmed with so much information. But I will recommend that you go through your textbooks and look into these mechanisms much more deeply to know much more information. Okay, so that’s all for today. I hope this video was helpful. See you again, hopefully next week, with a new topic of pathology. So until then, take care and goodbye. Thank you.

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