S C I E N C E

 Cancer is a disease like no other. We cannot compare it with an intruder because it is not an outside "genome" or an uninvited virus. Cancer cells start from within us, and I would dare to say that they are a part of us. They are us. Let's take an example of a person who suffers from a personality disorder. Some days, the individual behaves like their normal self and take care of their health. Some other days however, their disorder takes over, creating another character which attacks his own body. The person becomes an enemy of their own self. That is exactly how I would describe cancer. Likewise, cancer cells are our own cells that have undergone specific modifications.

It is important to note that our immune system has a mechanism called central tolerance which eliminates through the process of apoptosis, T and B cell clones before their maturation, only if they have receptors that recognize antigens (molecules) of the same organism with an affinity greater than one limit. Basically, this means that when some cells are produced that seem to deviate from the norm and include indicators about their abnormality, our system will recognize them and kill them. However, central tolerance is not infallible, and some self-reactive lymphocytes escape to the secondary lymph tissues. That is the reason why there is an additional security mechanism called the peripheral tolerance.

Taking all this process into consideration, could these or similar mechanisms eliminate potential cells that are prone to forming cancerous tumors?

NK cells: They have the ability to attack on any cell in the body that expresses abnormal or unusual proteins in its cytoplasmic membrane and thus they can destroy some cancer cells.

CTLs: their cytotoxic action enables them to destroy cancer cells.

In contrast of what these cells can do, cancer cells are still able to grow and keep multiplying. That happens because cancer cells end up being cleverer than NK and CTLs by developing mechanism allowing them to evade immune responses.  Similarly, the microenvironment surrounding tumor cells suppress the functions of our tolerance by tricking our immune response resulting in an uncontrolled cancer growth.

After a lot of observation, a simple question started spiraling in my head:  Do normal cells “give birth” to a cancerous offspring or the normal cell must first have some alterations itself, ending up in an between state of normal and non-normal in order to “create” the next generation of malignant cells? And if so, the in between state of this cell, could be the reason why it is easy for it to trick our immune system?

There have been some indicators that prove the existence of state called transformation. A cell that is transformed appears with alterations in its morphology. In some cases, this state can make the cell form tumors. The cell transformation is caused by mutations due to DNA alkylation agents such as busulfan, cyclophosphamide, dihydroxybusulfan or due to natural cytotoxic causes like ionizing radiation.

The first stage of the cancerous transformation consists of genetic mutations and after, the existence of some promoters which will define the direction of the transcription and will induce cell division will be the cause of the “produced cancerous offspring”. In a hypothetical scenario, where a transformative cell exists without its promoters, then there will be no cancer. Can a gene promoter ignore mutated genes and give the signal for the transcription to start after these regions? And if these regions are of outmost importance for the transcription to take place, then could the promoter or another molecule recognize the changes, and trigger apoptotic signals? Could we create such signals in the laboratory and insert them in one’s organism in order for them to detect suspicious transformed cells?

Although I have mentioned it before, some potential ways  one’s cells could undergo gene mutations, I must pay attention to the danger of some viruses. Some cancer types have been confirmed to be caused by a specific virus, even though some other types {such as leukemias} are considered still to be the result of an unknown agent. I personally have a belief that most of the cancer types are generated by a virus either to the person who suffers from cancer or from one of his ancestors. {This will be discussed in another article}.

Lets take an example of Simian vacuolating virus 40 (SV40). The virus after entering the human body, has his genome to be incorporated to the hosts DNA. The SV40 virus codes two prime proteins called large T and small T and both will initiate the cancerous cells transformation of the cells that have been infected by SV40.

Some other viruses that are related to carcinogenesis are: Epstein-Barr, HBV, Human T-lymphotropic virus type 1, Human herpesvirus-8 (HHV-8).

The last two viruses mentioned, are RNA viruses and in some cases, they contain peculiar genes called oncogenes. Let’s take an example of the Rous sarcoma virus which includes in its genome a specific oncogene named v-src.

V-src will code a protein kinase which will phosphorylate tyrosine residues in proteins. It has been shown that this process will activate the STAT family which has a very important role in growth factor, the RAS signal  {RAS/MAP is an intracellular signal molecule that induces cell proliferation and the existence of mutations in this molecule promote carcinogenesis} also mutations in the RAS molecule are detected in 30% of ALL and in 15% in MDS. This will result in a constant cell proliferation, mutations, and abnormalities in chromosomes.

{Could we deactivate the V-src gene in cancer cells in vivo?}

There have been some indications that oncogenes are not only produced by viruses.  In particular, Howard Temin, suggested that oncogenes can actually “live” in healthy cells and actually the virus can take these oncogenes from the host’s genome.  The host’s oncogenes were called proto-oncogenes or cellular oncogenes. In other words, proto-oncogenes, are genes which after mutation become oncogenes causing tumor growth. The main difference between proto-oncogenes and oncogenes is that proto-Oncogene are normal cells existing in an individual’s genome and they control the cell cycle and the cell division. They can be proteins regulating cell growth control, growth factors, growth factor’s receptors, signal transducers, intranuclear agents, regulators of cell dead. On the other hand, oncogenes are the malicious form of cellular oncogenes, often being created after mutations caused by ionized radiation, drugs or viral genome insertion. A oncogene caused by an RNA virus can contribute to the formation of viral oncogenes while oncogenes created by mutations and drugs can result in the creation of a modification in their expression such as overactivated proteins or an increased or decreased quantities of important factors.  Some examples of proto-oncogenes are the RAS molecules, Myc, Her2. Different kind of mutations can occur that will transform cellular oncogenes into oncogenes such as deletions, chromosomal translocations, point mutations, or extra chromosomal copies of a proto-oncogene.

Additionally, oncogenes have been classified in different subtypes regarding their role.

Starting off with one type of proto-oncogenes and their oncogenes which encode proteins that provoke cell proliferation. As a matter of fact, some of these proteins operate as growth factors or their receptors. One example of such oncogenes is the SIS oncogene of simian sarcoma virus (SSV) which can be found in the human malignant glioma. SIS will encode a form of platelets growth factor PDFG. Similarly, the erbB gene will encode a growth factors receptor, homologous to the EGF receptor. As it is expected, this inaccurate and different encoding of homologous growth factor or its receptor can result in an uncontrollable proliferation of the cell cycle. Furthermore, a constant encoding of transcription factors can end up in the same unrepressed growth.

Another type of proto-oncogenes are the ones called tumor suppressor genes, reducing the cell division’s speed by slowing it down. They operate with a negative regulation by encoding proteins that will stop the division, as well as trigger apoptosis when it is needed. Equally important is their role in repairing DNA mistakes. If tumor suppressor genes do not work according to their regulations or if they get deactivated DNA is more prone to mistakes, apoptosis is being avoided and cells can grow uncontrollably. A great example to such case, could be the retinoblastoma which is caused by the inheritance of a mutated allele. If the normal allele gets deactivated, then tumor cells will start occurring.

Moving on to the third classification of cellular oncogenes, we have genes holding the responsibility for apoptosis. These specific genes, encode proteins which either can activate or deactivate the process. Apoptosis is a function of extreme importance for our wellbeing. It is the way which the body is able to get rid of the unwanted cells. Not only aged cells can slowly die but also, it prevents from tumor formation and is crucial in immune processes, such as the development of tolerance and the destruction of target cells by cytotoxic T cells or by natural killer cells. For example, when lymphocytes continue to be activated by an antigen, the messages received during activation inhibit the corresponding apoptotic messages. As antigen levels decrease, apoptosis inhibition signals fade and lymphocytes begin to die. If cytotoxic cells do not die through apoptosis when they should, they will start attacking on the normal cells creating autoimmune disorders. An anti-apoptotic gene called  bcl-2 which is an oncogenic gene often found in non-Hodgkin lymphoma. This gene gets activated after a chromosomal translocation t(14;18). Lastly, a correlation was found between bcl-2 and Epstein bar since the virus seems to have a homologous gene which can function with a similar way and induce the apoptosis. Do we know if this similar virus gene existed prior to bcl-2 or it is a confirmation of Howard Temin’s theory where a virus can get its oncogenes from the hosts genome?

 In conclusion, one can say that cancer is a part of us that followed the wrong way. It seems that malignant tumors are not easy to be killed without killing us too. If cancer was triggered by a virus, an atomic bomb which affected near areas with people’s genes undergoing mutations and then inheriting it to their offspring or some specific medications then we could say that it is indeed say that it is an invader that lives silently within us until it suddenly takes its toll. However, could cancer exist without any of these? To be a sincere malfunction of our own cells? 

Sources :

-My own notes

-The book : Kuby Immunology

-https://www.ncbi.nlm.nih.gov/books/NBK547849/

-https://www.nature.com/articles/1203912

-https://www.wikigenes.org/e/mesh/e/19312.html

-https://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883/

 

Megakaryopoiesis

Starting off, this procedure begins as it is expected, with the HCS, the multipotent self-renewing cells. HCS will produce a multipotent progenitor (MPP) which is a common progenitor for every cell in our body. This cell will differentiate into our common myeloid progenitor (CMP) which is produce by its turn another cell which is the progenitor of megakaryocytes and erythrocytes (MEP).  Basically, MEP is the cell that will give of either erythroblasts or megakaryocytes. The development of these two, depends on the signals, the factors, and the microenvironment. As a matter of fact, some important transcription factors that must exist in the surrounding in order for the Megakaryopoiesis to start being produced, are GATA-1 is crucial for the differentiation and the maturation of megakaryocytes, FOG-1 which interacts with GATA-1 and activates or deactivates it, GATA-2, Fii-1 , Pu.1 with its decrease being a key to the normal development of megakaryocytes  and RUNX1. The maturation and the final production of platelets take place in specific places in the bone marrow and with the interaction of other molecules and growth factors.

In order for the common myeloid progenitor to start developing towards the megakaryocytes, one important hormone must be present. This molecule is called thrombopoietin, it is produced in the liver and it regulates platelet production.

EMP cells will eventually differentiate into BFU cells and at that time, thrombopoietin is that one molecule that will get activated and help BFU cells differentiate into CFU. BFU and CFU cells are morphologically the same since both of them are immature cells of the bone marrow, however in cultivation, only the CFU cells are able to form colonies.  Eventually, the CFU cells will differentiate into promegakaryoblasts which will give off megakaryoblasts and these cells will mature into megakaryocytes.

Megakaryocyte has pseudopods and a specious cytoplasm. In addition, it is an excessively big cell, and its maturation happens in two stages: The first stage consists of the typical mitosis and in the second, there is the proliferation of the nucleus while the cytoplasm does not get divided (Polyploidy).  This results in a size increasement (by endomitosis).

The pseudopods the megakaryocyte has, will get detached from it , the nucleus will endure apoptosis and will get phagocytized by macrophages. At that time, the cell exists near the venus sinuses and then they will release the platelets in the blood circulation. Platelets have no nucleus, but they consist of vesicles such as lysosomes and alpha granules. 

https://www.sciencedirect.com/science/article/abs/pii/S0037196310000326

 Monocytes & Dendritic cells

Monocytes and dendritic cells are both considered to fall under the spectrum of myeloid cell line. They obviously share the MPP progenitor as all of them cells in our body, and also share the myeloid progenitor cell which will eventually differentiate into the granulocytes/macrophages progenitor (GMP). GMP cell will mature into monocytes/dendritic progenitor (MDG). One molecule which seems to separate which cells will be produced (monocytes or dendtritics) seem to be Ly6C+ cell. It is claimed that this cell appears both in the marrow and in the spleen and triggers the production of monocytes.

 

Monocytes

Monocytes are able to circulate in the blood for about 8 hours, increasing in size. After their enlargement, they migrate to different tissues and differentiate into macrophages. This differentiation process consists of the increment of their  organelles both in size and complexity and they also gain a high phagocytic capacity with the ability to produce higher levels of hydrolytic enzymes and a variety of soluble agents.

 

Dendritic cells

They have elongated cytoplasmic projections on their surface, and they are many different types of those cells.  Their main categories are: Langerhans cells, intracellular space cells, monocyte-derived dendrites, and plasma cell-derived dendrites. Each type of dendritic cells has different functions  of trapping the antigen in one area and presenting it in another place.

 

Lymphopoiesis

Lymphopoiesis is the creation of lymphocytes. These cells circulate all the time in the blood and in the lymph. As a matter of fact, the lymphatic system is one of the most important systems in our body because the lymph, originates from tissues and it slowly filters into the lymph node, piercing the cortex, paracortex and marrow, and gives phagocytes and dendritic cells the ability to trap bacteria or other antigens, which have been transferred by the lymph. If the same antigen invades again into our body, the lymph will immediately leave the lymph node while being filled with antibodies. The lymph that exists the lymph node, contains way more lymphocytes than the lymph that enter the lymph node. Lymphocytes are divided into three main categories: B cells, T cells and NK cells. Basically, those three cells have different molecules on their membranes surface.

T lymphocytes mature in the Thymus and during this procedure the T cell expresses on its membrane a molecule that binds antigens which is called T cell receptor (TCR). Those receptors are able to recognize antigens only when they have been connected with membrane proteins named Major Histocompatibility Complex (MHC) molecules and they are genetically diverse glycoproteins. After an antigen binds with MHC molecules, it will get recognized by some T cells, which will eventually start to multiply and differentiate into effector cells and T memory cells. It is important at this stage to distinguish, the three main different “subpopulation” of T cells: T helper cells, cytotoxic T cells and Regulatory T cells (Tregs).

T helper cells:  These cells contain a surface glycoprotein called CD4. After the presentation of an antigen connected with an MHC molecule the T helper cells are the ones starting to differentiate into the effector cells. Alternatively, the T helper cells can also differentiate into T memory cells which are responsible for the long-term immunity obtained against many pathogens.

Cytotoxic T cells:  The are part of the effector cells and  are recognized by their surface glycoprotein called CD8. Their utmost importance job is to monitor the body’s cells and kill the ones that present an antigen (always bonded with and MHC molecule I). For instance, such cells can be cells infected with a various, *cancer cells and a foreign tissue from a transplanted organ. 

Regulatory T cells:  They are identified by the presence of both CD4 and CD25 molecules in their cell membrane. However, Treg cells suppress immune responses, they basically are negative regulators of the immune system. It has been claimed that some members of the Treg cell subpopulation may be ancestors of the memory cells.

 

B lymphocytes mature in the bone marrow, and they compose and express some membranes molecules called antibodies or immunoglobulins (membrane bound immunoglobulins). These cells have receptors on their surface membrane called BCR and they are able to bind with antigens without the presence of MHC molecules.

 When a B lymphocyte cell interacts with an antigen for the first time, the cells start to get divided very quickly. It starts to differentiate into B effector cells which are called plasma cells and memory B cells. Memory B cells have a longer lifespan than B virgin cells and express the same membrane immunoglobulins as their parent cell. In addition, Plasma cells produce immunoglobulins in secretory form and have little or no membrane immunoglobulins. As a matter of fact, they are in the final stage of maturation and do not divide furthermore. However, they die within 1 or 2 weeks.

 

Nature killers (NK) cells are large granular lymphocytes and appear to have the ability of expressing cytotoxic activities against cancer cells and some virus infected cells. Nevertheless, it has been indicated that they do not contain receptors nor immunoglobulins. At the same time, an NK cell has receptors that allow the recognition of abnormalities, like the decrease of the expression of MHC class I molecules or the appearance of an unusual expression pattern of surface antigens, by some cancerous and virus-infected cells.

Some cancer cells express molecules that are foreign to our body. As a result, the immune system, triggers a respond by producing antibodies. These antibodies are called anti-cancerous (or anti-viral in case of virus-infected cells) antibodies that bind with the target cells. The NK cells, express a membrane receptor called CD16 which is designed for a specific region of the antibody molecule, and has the ability to bind to these antibodies  causing the destruction of target cells. This is known as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

Sources :

Kuby immunology