[MUSIC] Hi, my name is Dr. Jelani Zarif and I am a prostate cancer researcher at Johns Hopkins University School of Medicine in Baltimore Maryland. Today I'm going to talk to you about the ten cellular hallmarks of cancer. These ten cellular hallmarks are what distinguishes a normal eukaryotic cell from a cancerous cell. Here are some of the learning objectives of this module. First, students will be able to list and understand the ten cellular hallmarks of cancer, understand how these cellular hallmarks distinguish a cancer cell from a normal human eukaryotic cell. Lastly, articulate how these hallmarks make a cancer cell more fit or competing, surviving and reproducing in its host, which is the human body. Before we go into the 10 cellular hallmarks of cancer, here are a list of terms that will be used interchangeably throughout the lecture. Apoptosis. Apoptosis is a form of programmed cellular death. Mitosis. Mitosis is a form of cellular division that results in two daughter cells. Telomere. These are sequences located at the ends of a chromosome. These have specific sequence of nucleotides and these sequences shorten at the end of each mitotic cell cycle. Angiogenesis. Angiogenesis is the process of developing new blood vessels from preexisting ones. And finally metastasis. Metastasis is the process by which a cancer cell or cancer itself spreads from its origin to another part of the human body. Now that we have covered several terms we will discuss the first five cellular hallmarks of cancer. We will also discuss how the cellular phenomenon differ from a normal human eukaryotic cell. So before we discuss cellular hallmarks, let's revisit the eukaryotic cell. The eukaryotic cell is the smallest functional unit that can produce daughter cells in the human body. It's a word that comes from meaning small in Latin, and it is able to produce two daughter cells through a process called mitosis, and this process is tightly controlled. Cells are present throughout our human bodies that make up tissues and these tissues make up organs and so cellular homeostasis is very important in tissues and organs. The cells as you can see from this cartoon are made up of a number of organelles. One that's very prominent is the nucleus and the nucleolus shown in purple, as well as the mitochondria, lysosome, the centrosome, and other organelles located in the cytoplasm. Again, the production of cell's progeny is tightly controlled in the mechanism called the cell cycle. And here it is shown in a cartoon, the cell cycle is a series of events that take place in a cell leading to its division, and duplication of its DNA, known as DNA replication, to produce two daughter cells. In the nucleus of these cells the cell cycle is divided into three periods. Interphase, the mitotic phase shown by M in the cartoon, and cytokinesis which is shown in the cartoon of the two daughter cells, which occurs after the mitotic phase. During the mitotic phase again the cells split into two distinct daughter cells. During the final stage, cytokineses, the new cell is completely divided. To ensure proper division of the cell, there are several control mechanisms that occur during the cell cycle. These are known as cell cycle check points. These are located gap phases or the G phase is shown in a cartoon. This is germane to what distinguishes a cancer cell from that of a normal cell, and leads us to hallmark number one. Cellular hallmark of cancer number one is replicative immortality. Normal human cells have a finite ability to undergo mitosis due to what is known as the end replication problem. This is largely due in part to the telomeres of the chromosomes, which are the ends of the chromosomes that get shorter after each mitotic division. One of the first people to observe this was Dr. Lenit Hayflick. And when cells stop dividing, they are known to have reached Hayflick's limit. And once cells reach Hayflick's limit, they can no longer divide. And they go into the G0 phase of the cell cycle, also called cellular senescence. Here in this cartoon, you can appreciate the ends of the chromosomes are pink, those are the telomeres. And in normal cells they can stop dividing once the telomeres become too short. However, a hallmark of cancer cells is that they are able to greatly exceed what is known as Hayflick's limit and continue to undergo mitosis. Cancer cells can greatly exceed Hayflick's limit by using an enzyme known as telomerase. Telomerase is able to elongate telomeres after they get too short to sustain proliferation. And telomerase is seen to be expressed at higher levels in several cancer types. Here's a cartoon of telomeres. And it's an enzyme that's a reverse transcriptase enzyme that adds short nucleobases shown in a cartoon as AAUCC to the ends of the telomeres in a three prime direction. So hallmark number one was replicative immortality. By cancer cells being immortal, they are able to continuously proliferate, and also they can pass on genes to daughter cells that are mutated. This leads us to hallmark number two of cancer known as genome instability. In a previous lecture, Dr. Ahmed discussed that a gene was a unit of inheritance, that it consisted of two alleles. In this hallmark we will see how genome instability gives rise to tumor genesis. Hallmark Number 2: Genome Instability. In normal eukaryotic cells, they bare 22 autosomes and one pair of sex chromosomes that reside in the nucleus. In a normal cell undergoing DNA synthesis during the cell cycle, if it detects a mutation, which occurs in the gap phases of the cell cycle. The cell is able to stop the cell cycle, repair the mutation and then re-enter the cell cycle. Genes that are involved with stopping the cell cycle from mutation is detected, are known as tumor suppressors genes which was covered in a previous lecture. So think of these genes as being the brakes in your automobiles. If you see traffic coming, you put on the brakes to stop your car or your automobile. Tumor suppressive genes work similarly. However, cancer cells differ from normal cells due to their ability to bear an abnormal amount of chromosomes within the nucleus and also still be able to undergo mitosis. Genes that are mutated in cancer or lost in cancer contribute to genome instability. These are your breaks, known as tumor suppressor genes. Conversely, there are genes that become over expressed or mutationally activated And these are known as oncogenes, which was covered in the previous lecture. And these genes cause cells to proliferate uncontrollably. You can think of these genes as your Gas pedal. the gas pedal causes you to accelerate. Notable genetic alterations that occur in cancer, especially to oncogenes as well as tumor suppressor genes, are point mutations, deletion of chromosomes where tumor suppressor genes lie, as well as loss of heterozygosity, and several other mutations and modifications. Here is a look at genome instability in cancer cells using the molecular biology technique called karyotyping. This is a method to assess the number of chromosomes per nuclei. If you take a look at this karyotype from CML, you will appreciate the genomic rearrangements as shown by multiple colors on chromosome nine which is pink and white, and it's highlighted with the arrow. As well as a deletion in chromosome number 22, shown by the arrow. Normal cells will not bear such insults and continue to undergo mitosis. However, cancer cells are able to continuously divide and bear such mutations and genetic rearrangements. So this genomic instability leads us to our third hallmark, evasion of growth suppressor signals. Mitosis in normal cells is a tightly controlled process wherein the pro and anti-proliferation signals coordinate cell activities at the cell cycle level. Particularly the G1 phase of the cell cycle as a vital checkpoint wherein anti growth signals exert their influence to block cellular proliferation. However do to hallmark number two, genomic instability, most cancer cells are able to circumvent normal growth suppressor signals in the G1 checkpoint in order to continue to proliferate. Again, how cancer cells are able to evade growth suppressor signals. One mechanism is the tumor suppressor gene called retinoblastoma or Rb. Rb actively inhibits cell passage through the restriction point in the G1 cell cycle phase. Cancer cells with mutated Rb remove this gatekeeper or ongoing cellular proliferation. Another tumor suppressor gene called p53 is lost in many cancer types. This allows for the cell cycle to progress despite DNA damage and other cellular stresses that would kill a normal cell. With these gate keeper genes are lost or mutated, cancer cells are able to sustain proliferation and resist cellular death, which is hallmark number four. Hallmark number four, resistance to cell death. Normal cells can initiate cell death, also known as apoptosis in response to an abundance of DNA damage, DNA mutations, as well as other cellular stresses from external factors. As I stated in a previous slide, a cancer cell can continue to cycle through the cell cycle While bearing such DNA damage in other cellular stresses. Cancer cells are also able to resist cell death by up-regulating pro-survival proteins to avoid cell death in the presence of these stresses. One example of a pro-survival protein that's seen overexpressed in many cancer types is the pro-survival protein Bcl-2. Bcl-2 has anti-apoptotic family members such as Bcl-2, Bcl-XL, Mcl-1, CED-9, A1, Bfl-1, and also pro-apoptopic family members such as Bax, Bak, Bcl-Xs, Bim, and host of others. Here's a cartoon illustrating that. In many cancer types, we see Bcl-XL and Bcl-2 family members particularly over expressed. And that's shown here in the method used in molecular biology called immunohistochemistry. This is Bcl-XL that is over-expressed in lymphoma and you can appreciate the brown are Bcl-XL positive cells in this immunohistochemistry slide. Because cancer cells are able to resist cell death, they are able to sustain proliferation. With all the previous hallmarks, they are able to do this quite easily. Within normal cells, growth factor signaling is also tightly controlled for tissue homeostasis and other cellular functions. Cancer cells are very different and they have the ability to proliferate as I mentioned in Hallmarks 1 to 4 with loss of too much suppressor genes, as well as over expression of oncogenes, such as RAS, SARK, and many others. Cancer cells also have the ability to stimulate the normal cells that surround them in what is known as the tumor microenvironment to provide them with essential growth factors. One growth factor that's well studied in cancer research is called the epidermal growth factor. Epidermal growth factor can bind to the receptor, which is expressed on cancer cells known as EGFR, to activate an oncogene well-studied in cancer research called RAS. RAS can have a plethora of downstream effects that positively regulate cell proliferation of cancer cells. So here's a quick review over hallmarks three through five. So a normal cell compared to a cancer cell. So a normal cell, when it detects DNA damage, p53, a tumor suppressor gene stops the cell from cycling, puts the cell into cellular arrest, repairs the DNA, and the cell is able to go back into the cell cycle. That's one option. If there is too much DNA damage, the cell is signaled to go into apoptosis, and then the dead cell is then cleared by phagocytes, and this leads to cellular and genetic and tissue homeostasis. However, in cancer, there is a loss or mutation of p53 where it does not function correctly and when the cell has aberrant mutations, the cell is not able to leave the cell cycle. And instead it continues to proliferate and go through the cell cycle unchecked. It does not undergo apoptosis. And you get genomic instability instead. So here are the first five hallmarks that we have covered in this lecture. Hallmark number one, replicative immortality. Hallmark number two, genome instability. Hallmark number three, evading growth suppression. Hallmark number four, sustained proliferation. Hallmark number five, resists cellular death. So that is it for this section. I think you can appreciate the first five cellular hallmarks of cancer. You will now have a short quiz, and in the next session we'll discuss the next set of cellular hallmarks of cancer.
