The world's biggest enemy... cancer!

We all know that cancer is a humongous problem. It kills about 8 million people every year, and is the second leading cause of death globally! Responsible for every 1 in 6 deaths, this deadly sickness needs to go away and a treatment needs to found.

Here in my first article about cancer, I'll be diving deep into what cancer is made of, how it works, the inefficiencies in current treatments and some new innovative methods that could potentially end this devastating sickness.

Cancer is a genetic disease caused by detrimental variation in the genome which expresses genes that cause cells to mutate and infect other cells.

So first of all, what is cancer? Well, cancer is a genetic disease in which an accumulation of detrimental variation in the genome causes a cell to deform and infect other cells through a process called metastasis. A mutation is a detrimental genetic variation that can contribute to disease or cancer/ increase the risk of a patient developing this sickness. There are two types of cancer genes, oncogenes, which promote cancer and are high in cancer cells and low in normal cells and, tumor suppressor genes, which protect cells against cancer and are low in cancer cells but high in normal cells. Now inside of these genes there are two main types of mutations, activating and inactivating. Activating mutations, cause the genes to be expressed at the wrong time, wrong level, or with a new function and are usually found in oncogenes. Whereas inactivating mutations cause reduced function of a gene, therefore less RNA or protein is made, these mutations are usually found in tumor suppressors genes.

You can acquire a mutation in two different ways, somatic and germline. Somatic mutations are acquired by somatic cells, which are all the cells of the body, except eggs or sperm and those mutations are passed on to daughter cells during cell proliferation. It is important to remember that these mutations cannot be inherited by offspring. Every time a cell divides, it must replicate its DNA and errors just get made by chance. Just by chance, about 1 mutation is made every 10 billion base pairs.

Adding on, there is an increase in DNA damage and subsequent replication error due to environmental carcinogens as well. One example of this is UV damage, which is also shown in the diagram to the right where an incoming UV photon hits the DNA and damages it. So that it causes nics in the DNA which you can see to the far right, which then have to be repaired by the cell and this can cause an increased risk to skin cancer. Similarly, smoking causes chemical damage to lung cells, just as hepatitis and alcohol abuse can lead to damaging cirrhosis of liver cells.

On the other hand germline mutations (aka inherited mutations) are present in germ cells (egg or sperm) and are inherited by offspring - genetic variations we are born with. These mutations are also why offspring look so similar. For example, women who inherit a BRAC1/2 mutation are at increased risk for breast cancer and individuals who inherit a CHD1 mutation are at increased risk for stomach cancer.

Now that we understand what cancer is and how cancer mutations work, let's look into how cancer cells work in the body and what makes them different from normal cells!

Cancer cells have nine main hallmarks that make them different from normal cells and use a process called metastasis to move to and infect other organs!

Firstly, a cancer cell must survive by overcoming three processes, cell proliferation, cell survival, and cellular communication. With cancer cells they don’t self destruct but instead they replicate faster, whereas regular cells that just die once they have a bad mutation. This leads us into our first hallmark of cancer cells which is...

Hallmark #1: Cancer cells can produce very rapidly in the body.

Cancer cells can produce rapidly in the body and can pass on genes to daughter cells. They have the ability to exceed hayflick’s limit and continue to undergo mitosis because of this enzyme called telomerase, where they can elongate their telomeres unlike normal cells which have telomeres fairly short and which deteriorate during mitosis (cell division). Unlike normal cells which do not have this enzyme! 

Hallmark #2: Genome Instability.

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 cycle, repair the mutation and then re-enter the cell cycle. Cancer cells are different and can have an abnormal amount of chromosomes per cell and can bear mutations in their DNA with the ability to still undergo mitosis. Also they have oncogenes which are genes that become overly expressed and increase very rapidly and uncontrollably. Gene mutations that are observed in cancer cells delete chromosomes where tumor suppressor genes lie and allow for there to be more oncogenes, causing more bad mutations to be expressed.

Hallmark #3: Cancer cells can evade growth suppressor signals.

Regularly mitosis is a tightly controlled process in which we are able to multiply cells, and anti growth signals coordinate cell activities at the cell cycle. Whereas in cancer cells they can take out these gates and other tumor suppressor genes and replace them with oncogenes to allow them to replicate much faster and not die as well!

Hallmark #4: Cancer cells cannot die.

Adding on, another hallmark of cancer cells is their ability to avoid 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. 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. They are also able to keep on going and not die because of their ability to over express oncogenes. One growth factor that's well studied in cancer research is called the epidermal growth factor. Epidermal growth factors 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 regulates cell proliferation of cancer cells.

Hallmark #5: Altered Metabolism

Cancer cells use alternate methods to make sources for energy and alternative metabolic pathways. An example of this is how normals cells break down glucose to provide energy. Whereas cancer cells can convert glucose to lactate without using oxygen.

Hallmark #6: Tumor promoting inflammation conditions

Now in cancer cells we are able to use tumor inflammatory conditions seen in normal tissue cells and the immune cells provided by tumor cells with what they need to survive and undergo EMT. EMT also known as epithelial to mesenchymal transition is a process by which epithelial cells lose their cell polarity and cell to cell adhesion, and gain invasive properties to become mesenchymal stem cells and invade other cells. The early mutation in normal cells being invaded releases chemicals in the microenvironment that may lead to mutations and enable other cells to accelerate the formation of a tumor. Shown below is a diagram of EMT occurring in a group of 3 cells.

Hallmark #7: Avoiding of immune system

Cancer cells are also able to protect themselves from the immune system by inhibiting T cells that would normally attack these cells by up regulating a protein that is called program death ligand 1. This is a very vital protein in cancer cells that normal cells do not have!

Hallmark #8: Cancer cells can out go a process called angiogenesis

Since cancer cells need blood to survive they are able to make new blood vessels to provide necessary nutrients and oxygen, this process is called angiogenesis. This is done by using pro-angiogenic factors such as vascular endothelial growth factor, also called VEGF, to become activated in tumor cells, and signal to endothelial cells (cells that line the interior surface of blood vessels) to grow and make new blood vessels. Immune infiltrating cells such as macrophages can also secrete VEGF to induce angiogenesis. Without any reduction in strength, angiogenesis enables tumor expansion and local invasion through the delivery of oxygen and nutrients and production of growth factors that largely benefit tumor cells. The reason why cancer cells need extra blood and outgo angiogenesis is because they grow faster than normal cells and outgrow their source of nutrients. This process also allows provides a way for tumor cells to get into the bloodstream and move to other organs in the body, this is very key in metastasis, which is the growing of cancer cells from their primary tumor site. Below is a picture of angiogenesis occurring in the body.

Hallmark #9: Cancer cells can invade other cells and outgo metastasis

This is the most important hallmark of cancer cells as this is what allows them to infect other organs and spread to different parts of the body. The first part of this hallmark is how cell to cell and cell to extracellular matrix interactions are altered.

In cancer cells there are changes or loss of structural proteins that keep cells bound to the extracellular matrix. The extracellular matrix (ECM) is a collection of extracellular molecules secreted by support cells that provides structural and biochemical support to the surrounding cells, when these are bonded to cancer cells it gives them much more support than just one cancer cell on its own. There are also a loss of genes or mutation of genes that are seen in metastatic lesions, known as metastasis suppressor genes. These genes are different from tumor suppressor genes whereas you lose a tumor suppressor, you get tumor formation. When you lose these genes, you get metastasis. Adding on, you also have a recruitment of immune cells which then leads to epithelial-to-mesenchymal transition.

Now that we understand what makes cancer cells different from normal cells let’s look more into how cancer cells spread in the body, also known as metastasis.

Metastasis is when a tumor starts growing and its cells move from the primary tumor to a different organ. But the real question is how does metastasis occur in the first place?

Well firstly we have our primary tumor growth. Accumulated detrimental mutations cause a cell to start changing and have the following properties:

• Uncontrolled cell division
• No growth suppression
• Different metabolism
• Resistant to cell death
• Avoiding immune destruction

Now that our tumor cells start growing and becoming more harmful due to mutations the next thing that happens is angiogenesis. This is a process in which new blood vessels are formed from tumor cells. Since tumor cells grow more quickly than regular cells and outgrow their source of nutrients, blood, they make new blood vessels to provide necessary nutrients and oxygen. Newly formed tumor vessels tend to be leaky but these vessels provide a way for tumor cells to get into the bloodstream. They are able to make new blood vessels due to pro-angiogenic factors such as vascular endothelial growth factor. These become activated in tumor cells, and signal to endothelial cells to grow and make new blood vessels. Now that our tumor cells get into the bloodstream and have the nutrients they need, they start to undergo epithelial-to-mesenchymal transition (EMT). This transition allows cells to become more mobile and move to different organs in the body.

To describe the EMT process a little further epithelial cells are normal cells that are cuboidal stationary and have strong interactions with ECM and other cells. Epithelial cells are what tumor cells are before they are able to move. On the other hand, mesenchymal cells are stretched shape, mobile and have weak or no interactions with ECM or other cells. Overall this transition is what allows tumor cells to become less structured and have much more mobility to infiltrate other cells.

Now that our cells have much more mobility and can move to other organs in the body, the next question is how are they going to infect other organs different from their primary tumor site? Well this is where invasion comes in. Invasion is a process in which tumor cells break through ECM. Tumor cells break through the ECM during invasion and are able to migrate outwardly, away from their natural location. Invasion allows cancer cells to move toward blood vessels and this is done with help from angiogenesis and the newly formed leaky blood vessels.

Now that our tumor cells have broken through the extracellular matrix they must get into the bloodstream. This process is called intravasation and can be done two ways, passively and actively. Tumor cells can do this actively by pushing their way through enthodial cells, whereas they can do it passively by getting shed from a tumor and entering presumably leaky blood vessels.

Since our tumor cells have gotten into the bloodstream they must survive in circulation. More specifically they must traverse venous system, lungs, and arterial systems. Tumors that are circulating in the bloodstream are called circulating tumor cells or CTC’s. During this process CTC’s must also avoid the various processes of cell death, shear force of blood pressure, immune surveillance and detachment from ECM or other cells. They are able to avoid most of these obstacles through:

1. Luck
2. Certain receptors that allow cancer cells to seem like T-cells and their ability to mimic normal cell inflammation properties.

Since our cancer cells are in the bloodstream and have survived all of their obstacles they now must get out of the bloodstream to infect other organs. This is where extravasation comes in and is a process in which tumor cells get out of the bloodstream by either getting stuck inside of capillaries (very small blood vessels inside of an organ) and then squeezing out of the capillaries. Or by becoming attracted to a secondary site via secreted molecular factors and attaching to that organ. Once they get to a secondary site they become known as disseminated tumor cells.

The picture below demonstrates both methods of extravasation. The one shown in the left hand side is where the tumor cells keep on rolling and then get attracted to the organ via secreted molecular factors, and the method on the right hand side is the method in which the tumor cells get stuck inside of capillaries and then pass through to the organ!

These disseminated tumor cells become dormant or turn into a secondary tumor. Many dormant tumor cells (DTC’s) begin growing in the secondary site into metastatic tumors and may not begin to divide immediately when they get to their destination, they may go dormant and grow into a tumor later on.

After the dormant tumor cells start to divide again, the unregulated proliferation of cancer cells will then lead to tumor formation. The increased proliferation (despite angiogenesis) causes hypoxic, acidic, and nutrient poor conditions. Cancer cells with migratory abilities are able to thrive in harsh conditions and the metastatic cells then migrate to a secondary site.

Overall, metastasis is a very vital process in cancer and without it cancer cells would not be able to harm other cells and spread in the body. Now although this might sound crazy metastasis does not only allow for tumors to grow but can also harm the body in the following ways:

• Loss of tissue function in the metastatic site.
• Bleeding: up to 10% of advanced cancer patients experience bleeding due to metastasis.
• Pulmonary embolism: blocked artery in the lung due to the tumor cells moving during metastasis.
• Cachexia: weakness and wasting of body due to severe chronic illness.
• Systemic disruption of ion homeostasis (homeostatic regulation of these ionic gradients is critical for most functions). Due to their charge, the movements of ions across biological membranes necessarily involves facilitation by intrinsic membrane transport proteins, and this process is disrupted thereby allowing transportation and facilitation of cell circulation and communication to be broken.
• Infection: due to cancer damaging immune arsenal, or the cancer treatment. Cancer treatment can cause irreparable damage to the body and damages loads of cells needed for human growth.

As you can tell metastasis is a very deadly process and harms in the body in many ways, not only by growing tumors, but also by killing cellular communication, causing bleeding, causing infections in the body due to poor treatments, and by causing a patient to feel very weak!

Since we understand how cancer works and what it is, now let's look into how we are trying to treat it today and why these treatments aren't working.

Problem: right now we are trying to kill cancer cells through antibiotics and radiation therapy but this isn't working because, the treatments don't work on certain cells, aren't personalized and harm cells that we need to function.

As of now our main source of treatment is through antibiotics and radiation therapy but it obviously doesn't work since more and more people are dying due to cancer! Current treatments do not work because different bacteria had different pbps and they have different natures for example cancer cells have certain receptors which don't allow all drugs to work on them.

Secondly, because certain drugs such as chemotherapy drugs cause side effects and they also harm cells that we need to outgo certain functions in our body. Lastly, because the medication isn't personalized. Therefore if we're giving somebody a medication at a high toxicity and we're not giving them the right dosage that's personalized to their metabolizer they will die due to high toxicity of the drug inside their body.

But on the brighter side there are many new innovative therapies being created that can possibly end this deadly sickness!

Solution: we can insert new DNA into cancer cells, allow for current systems in the body to become cancer resistant, and use artificial intelligence to detect and kill cancer!

The first innovative treatment of killing cancer cells inside the body is DNA self assembly. By hybridizing DNA onto the surface of veins we can actually make vein cells harder, thereby allowing for cancer cells to die inside the body. As cancer cells need blood to survive they make new blood vessels to provide necessary nutrients and oxygen to their cells and infiltrate the healthy vessels in the body. If we make the surface of the vessel and vein cells harder as well as code for certain hydrogen bonds to form when sensing an invader/cancer cell coming, we would be able to kill the cancer cells, as they would lack the nutrients needed to survive! You can read more about DNA self-assembly in an article I wrote: https://www.dhirubhai.net/pulse/programming-molecules-disobey-chemistry-physics-ayaan-esmail/

Moving on, since cancer is a genetic disease what if we can insert new DNA into the cell and override the current DNA inside the cell to program it to turn back into a normal cell. Well this is what gene therapy promises! By introducing new genetic material into cells to compensate for abnormal genes or to make a beneficial protein we can reverse the mutations that express for cancer to be created. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy will be able to introduce a normal copy of the gene to restore the function of the protein and turn it from a cancerous cell to a normal one. Below is a picture showing how gene therapy gets into cells and inserts the DNA.

One innovative method of detecting cancer can actually come from artificial intelligence. By using machine learning models to look at past data of pictures of tumor cells in the body, we can allow them to compare pictures of tumor cells from patients that have already developed cancer, to patients that might develop cancer, to see the probability risk of cancer developing. Therefore if there is a risk of cancer developing we can treat it from its early stages compared to if we wait for the tumor to metastasize and become bigger.

Now, this isn't some sort of fancy sci-fi detection method I am talking about, it's actually happening as we speak! Just a few months back Googles research team created a computer vision algorithm, which is an algorithm created to allow for computers to gain high-level understanding from digital images or videos, to detect breast cancer in the slide images of a patient's tissues which had a 89% accuracy compared to the 73% accuracy of a trained human pathologist!

Overall, cancer is a very deadly disease and a cure needs to be found! With new emerging treatments we might be able to find a cure sooner than most of us thought, but as of right now cancer continues to metastasize and grow in its death count.

Key Takeaways:

• Cancer is a very deadly sickness that kills loads of people every day and we need to find a cure as soon as possible!
• Cancer is a genetic disease and is due to detrimental variation in the genome that causes abnormal cell growth and mutations, which allows for non harmful cells to turn into cancerous cells.
• Cancer cells spread in the body through a process called metastasis in which tumor cells move from the primary tumor to a different organ by infiltrating blood vessels and regular cells.

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