The Mechanical and Chemical Stages, Cancer Cells Go Through

Aleyna GÖKÇE Aydın Utku ÇETİNER Bilgehan YILDIRIM Buse ÇAVUŞ Kübra YAŞAR Sude AKALIN Yiğit Emre ALTIN

WHAT IS GENOMIC STABILITY AND WHY IT HAPPENS?

To explain briefly the meaning of this. We can use this explanation; Genomic instability is usually seen as an alteration of genomes caused by several reasons. These reasons being mostly defections in surveillance mechanisms, DNA damage checkpoint, DNA repair machinery, and the mitotic checkpoint. If we go into the causes of these damages.

What are Examples of Causes of Genomic Instability?

Causes of Genomic instability can be both environmental reasons and inherited defects. Long exposure to factors that corrupts genome integrity like radiation, biological agents, and chemicals, can cause genomic instability due to environmental reasons. In short, we can keep the reasons under 2 headings.

Although all the protections are done by the cell and mitochondria to prevent the tendency of building damage over time, still lesions that cause genomic instability to happen. To ensure copying the DNA is right when passing down to the daughter cells, S-phase is a crucial point in DNA replication. Also, Mitosis is a highly complex event that takes place right after the G1 phase. İf in this process while the spindle assembly checkpoint (SAC) mechanism malfunctions in the control of the events of chromosome’s attachments to spindle microtubule’s and segregation, this can result in chromosomal instability(CIN). The majority of malfunctionings in mitosis are caused by CIN which forms the reason for almost %90 of all human tumors.

Replication stress which can be caused by oncogene activation can lead to susceptible cells with tendencies to be cancerous by initiating a mutation.

Living beings, to prevent as much as DNA damage, have evolved various mechanisms. These are called the DNA damage response(DDR).*

*DNA Damage Response

DDR mechanism is made by cellular pathways that can sense, signal, and repair DNA lesions which prevents highly harmful mutations to mostly happen by monitoring surveillance proteins that monitor DNA integrity and DNA repair pathways in response to DNA damage.

PERPETUAL (UNFORESEEN) GROWTH OF CANCER

Cancer is a disease that occurs with the unbounded division and proliferation of cells and is an effect of environmental conditions. It occurs when the control of normal cell growth is impaired. Increase and death of cells in normal tissues are in equilibrium. This balance is disturbed in cancer; apart from that, uncontrolled cell proliferation.

In all types of cancer, some of the body cells begin to divide steadily and spread to surrounding tissues. Cancer can start almost anywhere in the human body, made up of trillions of cells. Normally, human cells grow and multiply to create new cells when the body needs it. Cells die when they age or become damaged, and new cells replace the dying cells; however, when cancer develops, this orderly process is disrupted. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells emerge even if they are not needed. These extra cells can divide without stopping and form lumps called tumors. Many cancers produce solid tumors with tissue mass. (Leukemia-like blood cancers do not usually form solid tumors.)

Cancer core tumors are malignant, which means they can spread or invade nearby tissues: Also, as these tumors grow, some cancer cells can break off and travel to distant places in the body through the blood or lymphatic system to form new tumors away from the original tumor. The capacity of normal body cells to grow and divide is limited. Nevertheless, cancer cells start to multiply and grow by dividing uncontrollably.

TUMOR-PROMOTING INFLAMMATION

Fibroplasts associated with cancer; They contribute to tumor formation by stimulating an environment that will support the increase of cancer cells, angiogenesis and tumor formation. Tumors usually occur at the site of chronic inflammation, such as smoking causing lung cancer or stomach cancer associated with Helicobacter, etc.

Tumorgenesis is a; cell-autonomous process involving genetically transformed cancer cells.

Apart from these, immune cells have an important role in tumor formation, increase in growth factors, cancer cell proliferation, etastasis and angiogenesis event. Another part of great importance for tumorigenesis are fibroplasts associated with cancer; Fibroplasts promote tumor growth by inducing angiogenesis, taking up progenitor cells and reshaping the extracellular matrix. Tumor necrosis factor (TNF) -a is a cytokine produced by T cells. TNF-a stimulates both pro and anti-apopotic signals in microphages and other cells in the environment.

Another regulator of inflammatory processes that are closely linked to chronic inflammation and cancer is TGF-b.

As a result, tumors occur more frequently in the microenvironment and in a host disturbed by inflammation. Antigen-specific cytotoxicity is blunted by CD8T cells, while the same tumor antigen is given to the same tumor antigen, as a result, the inflammation rate is unchanged or even increased: Therefore, most of the cytokines involved in regulation are fed by various cells or contribute to their development.

EVADING GROWTH SUPPRESSION

The correct cell cycle has a molecular pathway and many checkpoints that suppress growth and cellular proliferation against stimuli that could damage DNA. Cancer cells must escape from these checkpoints in order to proliferate: This escape is an important difference of cancer cells from cells that develop correctly. There are several important pathways involved in the growth process. These are: p53, phosphatase and tensin homolog, hippo, Rb (retinoblastoma protein), GDF15 (growth differentiation factor 15), IGF (insulin-like growth factor) and KLF5 (krüppel-like factor 5) etc. Abnormalities in these pathways trigger mutations, so genes that prevent the growth of damaged cells should not be suppressed; it even causes the activation of genes involved in cell growth. (This may be the result of prolonged exposure to certain environmental chemicals.)

To give an example of these chemicals; cigarette smoke, benzo (a) pyrene for p53; Ethyl benzene, gasoline, chloroform, chromium, nickel, inorganic arsenic, acetaldehyde for Rb; in general, heavy metals, tobacco products, such as radon, benzo (a) pyrene, sodium arsenite (NaAsO2). Mutations occur in the growth suppressor pathways of chemical substances described above, thus causing uncontrolled growth of cancer cells. With the development of genetic testing techniques, mutations in genes that produce receptors involved in growth have been identified and drugs have been produced against these mutations.

AVOIDING IMMUNE SYSTEM

The immune system protects living things from pathogens such as bacteria, viruses and fungi that may come from the external environment. Many different immune system elements take part in this process. For example, there are many types of cells such as natural killer cells, T cells, macrophages, and B cells. However, sometimes these cells cannot recognize or affect the cell types they need to destroy. This leads us to the system avoidance feature of hope, which is one of the 10 hallmarks of cancer. cancer cells have developed many molecules or pathways to escape from the immune system. The first avoiding immune system way is that PD-L1 and PD-L2 transmembrane protein. This protein exists in normal cells and its purpose is that provide recognition between immune system cell and tissue cell and because of this recognition, immune cells don’t attack normal cells. But in the abnormal cell, this protein does not exist so immune cells can recognize this abnormal cell and attack them and destroy them. However, interestingly, a cancer cell may have this membrane protein. Therefore, this cancer cell because of their transmembrane protein can bloke T cells and defend themselves from immune system.

The second avoiding immune system way is that TIM-3 molecule (ligand). This molecule binds to TIM -3 receptor that is on the T cells surface and makes T cells exhausted and became useless. Cancer cell produces this molecule to protect themselves from T cells via inhibiting T cells.

The one of these molecules is lactate. Lactate is not only a by-product of the altered metabolism of cancer cell, but it also provides angiogenesis and reduces the activity of the immune system.

ANGIOGENESIS INDUCTION

Angiogenesis is the process of new vessel formation formed by budding of existing vessels. It causes tumor cells to grow more than they should, depending on the angiogenesis process. In addition, Angiogenesis also occurs in physiological and pathological conditions. In Cancers; Angiogenesis occurs pathologically in many eye diseases and inflammatory diseases.

One of the most common features in cancer cells is the extension of new vessel formation. Cancer cells need vascular formation to spread to different tissues and organs. At the same time, since cancer cells grow and multiply faster than other cells, they need more energy and removal of waste materials. Angiogenesis is essential for the growth of tumors as well as metastasis.

With the growth of cancer cells, their need for nutrients increases and they stimulate angiogenesis with substances secreted by tumor cells. There are many factors that stimulate angiogenesis. The most important of these are VEGF and bFGF growth factors. Angiogenesis is balancedly controlled by angiogenic factor in tumor growth. Proteases are responsible for the regulation of this balance.

The veins in cancer cells are different from normal veins. Therefore, cells and vessels are taken as a target. In the studies conducted, treatment methods are being developed to prevent new vascular extension. Chemotherapy is used in such studies, but some cancer cells show resistance to it. For this reason, since the vascular structure in endothelial cells does not change much in the formation of vessels, appropriate drugs are used. In addition, anti- angiogenesis therapy is applied in many tumor cells together with chemotherapy drugs. It has been observed that anti-angiogenesis therapy can be effective with the control of long-term tumor cells.

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