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/