Destruction of adjacent tissue, and metastasis

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What is cancer?

Cancer is a class of disease in which the cells display uncontrolled growth, destruction of adjacent tissue, and Metastasis. These are the malignant properties of cancer. The branch of medicine concerned with the diagnosis, treatment, and prevention of cancer is known as Oncology.

Cancer affects people at all ages, also foetuses. Cancer causes about 13% of all deaths. Cancer is caused by abnormalities due to the effects of carcinogens[1], such as tobacco smoke, radiation, chemicals, or infectious agents. If it is not treated , then tumour can cause some problem by aggressive attack on the normal tissue (nearby) or something to happen on the other body structures . There are different type of cancer because there are more number of body cells in our body. For example, cell that make up the lungs can cause a lung cancer . Different cells are present in lungs, so these may cause different types of lung cancer.

Normal cells

Our body is made up of billions of cells which can been seen under microscope. To make up the tissue and organs of our bodies cells should be grouped together. Because of the different type of body cells different type of body tissue can be made. For example there are bone cells in bone and breast cells in breast.

Genes and cancer

The different types of cells in our body has various job, they all have a centre called as nucleus. Genes are present inside the nucleus. Genes are actually bits of code. The information they carry can be switch ON or OFF. Cells are controlled by genes ,they decide when it will reproduce what it does and even it will die.

Benign and malignant tumours grow quite slowly and do not spread to various parts of the body. It has covering that is made up of normal cells. Benign tumours are made up of cells, which is quite small when compared to the normal cells. This will cause a problem if they are very large, uncomfortable , if they press on other body organs, if the space inside the skull is taken, or due to the release of hormones that affect the body function.

Malignant cells is made up of cancer cells that grow faster than normal cells and spread through and destroy the nearby cells. These cells spread to other parts of body.

There are many types of cancer that are named after the organs or tissue where they proliferate. The abnormal, unwanted cells may form a lump, called a "tumor" (or solid cancer), or they may be dispersed throughout the body which is the case with blood cancers or cancers of the lymph system (called non-solid cancers).

Primary and secondary cancer

The cancer present at one place is known as 'primary cancer'. However, the cancer cells can spread; they can break and get carried in the blood to all parts of the body as soon as they start to grow new tumors. At the same time the nearby cells also gets affected. For example,

  • Lung cancer can spread to the lining of the chest, the pleura.
  • Ovarian cancer can spread to the lining of the abdomen

A tumor from cancer, which is spread over a body, is known as secondary cells. Cancers from different cells types express different characters. They show differences in the speed of growth, various effects, and shows response to the drug used.

Cancer causes different symptoms to different people according to the place where they are. This is an information how cells and tissues grow body tissues when the number of cells increased the body tissue grows. The cells are reproducing themselves exactly for example one cell divide into two and two divide into four like is increased. This is happening mainly for the young people. All cells cannot be able to reproduce because some of them are matured it do only the particular job. However, there will be some immature cells around to replace or damage the cells. When our body needs more number of cells at that time, cells get double up increase. Every cell has a natural ability to stick together in exact place. The cell is nothing but a cell adhesion. The surface of the cell is molecules it is like a code. It make very difficult for cells to move to the wrong place. Cancer cells are different from normal cells, they are very important in number of ways.

Getting any particular type of cancer is nothing but a 'life time risk'.

Even though the success of cancer treatment has greatly improved and about 50% of cancers can now be cured, cancer is still a huge medical challenge.

How do we get cancer?

Genes in our cells contain instructions that control the way cells behave. If there is any damage or any changes to the genes, they can affect the way our cells grow and develop. Cancer is the disease caused by abnormal cells multiplying out of control.

There are cancers that are caused by genetic changes due to behaviors such as smoking, eating an unbalanced diet, or taking in too much alcohol. Other causes include factors in our environment, such as toxic chemicals, and viruses. Many causes of cancer are still unknown. Inherited genes may also increase the risk of developing certain types of cancer such as the case of breast cancers were some women inherit a gene that makes them more likely to develop breast cancer.

Cancer and the immune system

The body has its own natural way of defending itself, called the immune system. The immune system acts as a natural defense against diseases by destroying various harmful bacteria and viruses that enter our body. In order to perform this, the invading cells are recognized and labelled as "foreign" by the immune cells. Once these cells are labelled, special types of cells in the immune system enter theses foreign cells and destroy them. The immune system also detects cancer cells, as the cancer cells are different from normal cells. In many cases, these cancer cells are also destroyed before they turn malign.

Sometimes our immune responses to cancer cells fail which results in the cancer cells to grow continuously. This normally happens when the cancer cells are not recognized properly by the immune system, or these cancer cells tend to develop ways to cheat the system and avoid detection. Because of which these cancer cells are mistaken to be normal healthy cells.

No change in cancer type

The type of cancer does not change even if it spreads to one organ to another. For example, if someone has breast cancer and if that spreads to their lungs, they do not get lung cancer. The tumors in their lungs remain breast cancer tumors. The treatment they receive will still be for breast cancer, and so will probably be different from the treatment a person with lung cancer receives.

The cancer cells are constantly killed by the innate immunity system and this is one of the reasons why not all of us develop cancer. The researchers from the Wake Forest University School of Medicine and the Ludwig Institute for Cancer Research in New York, found out that some of us have a better natural immune response to cancer cells than others.

Some cancer statistics

  • Cancer statistics show that more than 1 person in 3 will get cancer at some time in their life
  • In the western world, the commonest cancers are breast, lung, bowel and prostate. Between them, they account for over half of all cases of cancer
  • Most cancers are caused by a gradual build-up of genetic damage in cells. This means that cancer is most common in older people. In general, cancer statistics show that the older you are, the higher your risk
  • According to the World Health Organization, at least one-third of cancer cases are preventable. The most effective ways to protect yourself from cancer are not smoking, limiting how much alcohol you drink, eating at least 5 portions of fruit and vegetables a day, keeping to a healthy weight, keeping physically active, and avoiding over-exposure to the sun.

Our immune system has many components which act together and create a system that can detect, destruct and remember foreign cells. Killer cells are one of the major components of the immune system. These killer cells eventually react with the foreign cells and kill it using chemical reactions.Innate cells and adaptive cells are the two types of killer cells. The adaptive immunity mostly depend on the T-cells which are cells that must be presented with a foreign protein in order to recognize it and kill cells bearing this specific protein. The innate system recognizes non-self molecules according to a specific pattern. This system is composed mainly of Natural Killer, PMN and Mast cells. Most of the immune response to cancer cells is mediated by the innate immunity system.

Researchers found that the degree of resistance to and the regression of cancer in mammals is affected by the innate immune system. This was done using cancer-resistant mice. In genetically engineered cancer-resistant mice, the leukocytes attacked the cancerous cells. After screening of these leukocytes, the scientists concluded that the majority of them belong to the innate immune system.

Some immune systems are able to recognize cancer cells with a higher efficiency; this recognition ability is different from one person to another. The innate immunity's leukocytes in the cancer-resistant mice recognize some molecules that are present in cancer cells; this ability makes their immune system more efficient in fighting cancer. Some of the leukocytes were transferred to wild-type mice, making them as resistant to cancer as the original cancer-resistant mice. Transferring these resistant white blood cells may enable developing a new method for treating cancer.

Application of this method in humans in a big question to be answered now. In a successive research including more than 100 people, blood samples were examined to determine their ability to fight cancer cells. A huge difference in the ability to kill cancer cells was found between different individuals. Some people's white blood cells managed to kill more about 2% of the cancerous cells, while others managed to kill about 97%, in less than 24 hours. Determining cancer-resistant humans with leukocytes that easily recognize cancer cells looks like a possible task. All that is needed is to discover a safer way to transfer these cells between individuals

Innate and Adaptive immunity A comparison

The immune system has two subsets, the innate immune system and the adaptive immune system, these two systems interact in a complex and dynamic network to protect the body against all the foreign pathogens and also maintain self tolerance. The innate immune system is called as the first line of immune defence against pathogens. Examples of innate immune system are granulocytes (neutrophils, basophils, and eosinophils), dendritic cells (DCs), macrophages, natural killer cells (NK cells) and mast cells, they express germline encoded pattern-recognition Toll-like receptors (TLRs) by this they recognize molecular patterns like lipopolysaccharide (LPS), lipoteichoic acid (LTA), mannans, unmethylated CpG DNA motifs and glycans, which are found on microbes, these are not found in self-tissues.

When the TLRs are activated, it triggers a chain of intracellular events, which includes NF-jB signaling pathways, this increases the production of proinflammatory mediators, increased nitric oxide synthesis and antigen presentation. Thereby induce activation of more and more leukocytes. The central event that takes place after the incidence of the pathogen is the complement system activation which involves a complex of more than 30 serum proteins and cell surface receptors, Complement system activation and immune complexes activation result in destruction of pathogens, opsonisation, phagocytosis, and immune complex clearance. This forms the first line of defence against pathogens that affect the body. This process also activate more specific adaptive immune response also.

In innate immune response, the immune cells expressed germline encoded receptors, but in adaptive immune response the T lymphocytes and B lymphocytes, express antigen specific receptors. The random rearrangement of the T cell receptor and immunoglobin (Ig) gene segments generate T cell receptor and B cell receptor which produce T and B lymphocytes providing the broader response to pathogens when compared to innate immune system. The two major T lymphocyte subsets are CD4+ T cells (helper T cells) and CD8+ T cells (cytotoxic T cells). The T cells are activated by interaction of their receptors with nonself antigens, which are presented by the major histocompatibility complex class II and I . The activated T lymphocytes start effector functions like cytokine production, CD4+T cells for b cell help and CD8+T cells for cytotoxic killing of cells expressing specific antigens. The B lymphocytes start their work by identifying soluble antigens, receive signals from helper T cells for their complete activation.B cell complete their effector functions like secreating antibodies with similar antigenic specificity as like B cell receptor.

Clonal expansion of antigen specific lymphocytes is started to obtain sufficient amount of antigen specific T and B lymphocytes to fight against the infections. The primary adaptive immune response kinetics is slower than the innate immune response kinetics but during primary adaptive immune response the lymphocytes subsets give rise to memory cell on the first incidence of infection and this memory cells helps in fighting against the same antigen again. This increases the effectiveness of immune response when compared to the innate immune response

Interaction between adaptive and innate immunity

Eventhough the adaptive immune system and the innate immune system have separate defence mechanisms, different in their immune cells, antigen specificity and response kinetics. They are very much dependent on each other. Efficient immune response is possible only through the interaction between the two immune systems. Any deregulation in their interaction may result in serious consequence for the host. The interaction between the two sets of systems is mediated by immune subsets and their soluble factors. The innate immune system activates the adaptive immune system during acute inflammatory reaction. In chronic inflammatory reaction the adaptive immune system regulates the innate immune system. By this it is evident that the there is tight interaction between the innate and adaptive immune responses for the effective functioning of the immune system

Mechanism of immune response against cancer

The immune system respond to the cancerous cells in an inadequate manner. The reason behind this inadequate respose is due to the variety of mechanisms used by the tumor cells to mislead the immune response and there by preventing the detection of tumor cells .This is the reason why the there is a problem in developing a suitable cancer vaccine

A strong host immune system is required to fight against the tough cancer cells. In order to start the immune against the tumor cells, the tumor cells must be recognized as modified self cells. The tumor cells exhibit antigen derived peptides coupled to class I MHC molecules. The tumor cells carry two types of antigens Tumor-specific transplantation antigens (TSTAs) and Tumor associated transplantation antigens (TATAs). The tumor specific transplantation antigens (TSTAs) are present in tumor cells alone. The TSTA help the host immune system to identify and destroy the tumor cells. The Tumor associated transplantation antigens (TATAs) are present in low levels in normal cells or in fetal cells. The TATAs are present in fetal cells in their development stage and later expressed only in cancerous cells are called Oncofetal tumor antigens. Oncofetal tumor antigens associated with cancers are Alpha-feto proteins (AFPs) and Carcinoembryonic antigen (CEAs). As the TATAs are present in some self cells they are less immunogenic than TSTAs

The activation of host immune system takes place when CD8+ T cells join with the peptides present on the tumor cells and when B7 on the tumor cell join to the CD28 of the T cell.

T Cell Receptor/MHC Class I Complex

Mike Clark's Immunoglobulin Structure Homepage

The B7 protein is not present in all the tumor cells, due to this reason the activation of host immune system fails. So the tumor cells lacking the B7 protein have to bind T cell receptor either to CTLA-4 or CD28. The CD28 binding to the tumor cell activates the host immune system. After this binding the CD8+T cells induces the Cytotoxic T lymphocytes to release perforin. Perforin creates pores in the tumor cell membrane. The formation of pores in the tumor cell membrane affect the ion concentration in the tumor cells and paves way for the entry of tumor necrosis factor. This response is called the CTL response or CTL activity

The tumor cell destruction is also carried out by the Natural killer (NK) cells and macrophage cells.A wide variety of tumor cells are affected by the NK cels because they are not restricted by the MHC. NK cell have a Fc receptor which binds to a tumor cell and helps in antibody-dependent cell-mediated cytotoxicity (ADCC). In the case of Macrophages they are activated by the IFN-g and macrophage activation factor (MAF). By this activation the macrophages release lytic enzymes into tumor cells and inhibit the growth of tumor cells

The tumor cell with high level of immunogenic antigens can also escape from the detection by host immune cells. The tumor cells have the capability to down regulate their expression of Class I MHC. They have glycoalyx molecules, which are used to hide the cell surface antigens. The anti-tumor immune response is suppressed by the tumor products and acquired resistance may also develop against immune effector mechanisms. Tumors have many undetectable ways of escaping from the host immune system.

There is a belief that immunosurveillance, cell monitoring regularly takes place in the body. But it is not proved experimental, the theory of immunosurveillance, is under research

  • http://www.brown.edu/Courses/Bio_160/Projects1999/cancer1/imm.html
  • http://www.cumc.columbia.edu/dept/ps/2007/immuno/im23.pdf

Immune Surveillance and its evidence

Immune surveillance theory is all about the presence of immune cells that can detect and destruct the cancer cells. If there is no such surveillance mechanism, then the number of tumors in animals would increase

Evidence for immune surveillance:

  • immune response is present even in advance cases, and can also have spontaneous remissions.
  • Tumor-infiltrating lymphocytes are found in the tissues mixed with tumor in melanoma cases,

Even though they are inactive and do not restimulate

HIV and post-transplant patients have suppressed T cell response and are susceptible to virally induced cancer. The HIV patients are affected by EBV lymphoma, Kaposi sarcoma and squamous cell carcinomas. Post-transplant patients take immunosuppressive drugs that inhibits the cell-mediated responses. So they are affected by EBV lymphoma, melanomas and sarcomas. The post-transplant patients, who have a risk of EBV lymphoma were treated with donor T cell infusion

The patients with cancer showed evidence of humoral response. IgM is the most abundant circulating antibody in cancer cells it was found that the generation of IgM was not due to T cell mediated response. They were unable to produce the effector responses similar to IgG , they are not involved in antibody dependent cell mediated cytotoxicity (ADCC) and like IgG they do not bind to Fc receptors

Experimental Evidence for Immune Surveillance:

Experiments were conducted in RAG knockout mice to find the evidence for Immune Surveillance

  • RAG knockout mice (RAG -/-), was tested, whether it is affected by cancer, it is resulted in occurrence of spontaneous cancers with higher frequency. This is because mice fail to develop mature B and T cells with out RAG, As RAG is the recombinase gene responsible for BCR and TCR gene recombination.
  • In wild type mice tumors were induced with the carcinogen, methylcholanthrine and then the tumors were inserted in other wild type mice. This resulted in tumor growth in the other wild type mice
  • After this the same procedure of transferring tumors induced in wild type mice were introduced into RAG knockout mice,this resulted in tumor growth in the RAG knockout mice
  • Again tumor growth in RAG knockout mice were introduced into other RAG knockout mice, this also resulted in tumor growth in the RAG knock out mice
  • When the procedure of introducing tumors from RAG knock out mice was carried out in a wild type mice, there was a little growth in tumor after this immune response was induced then rejected in the wild type mice

CONCLUSION:

In the study conducted tumors which developed in RAG -/- hosts when introduced into wildtype mice were rejected in wildtype mice. This rejection may be due to the reason that the tumors which develop with antigens would have lead to rejection due to intact immune system.This gives evidence for immunesurveillence

Another set of experiments were carried out in mice with out the receptor for interferon gamma (INFγR)

  • Increased incidence of tumors was observed in Mice deficient in the receptor for interferon gamma (INF?R),when they were tested for their susceptibility to tumors
  • After this a wildtype tumor with the INF?R was introduced in a wildtype mouse, and it showed tumor growth
  • Then a tumor without INF?R (INF?R -/-) was introduced into a wildtype mouse and it showed tumor growth
  • After this INF?R was put into an INF?R -/- tumor, and then that tumor was introduced into a wildtype mouse, this resulted in growth of tumor initially, then an immune response was initiated and rejection of tumor occured

Conclusion:

In this study, we can come to a conclusion that the interferon gamma receptor plays a key role in mediating immunologic rejection. The INFγ induces antigen presentation and INFγ receptor mediates the effect of INFγ. Tumor cells which have the INF? receptor have the capability of responding to signals to positively regulate antigen presentation. This is why when the tumor antigen is shown to the host and it resulted in tumor rejection .Compared to the previous study this was not the result in the RAG knockout mice.

Homeostasis:

For the homeostasis to occur it is vital to have intact innate response. The innate cells (NK, NKT, γδ T cells) must have the ability to produce INFγ. INFγ positively regulate on the tumor cells to enhance antigen presentation, on blood vessels to stop angiogenesis, and start TH1 and CD8 cellular immune responses.The intact adaptive response especially CTLs is also important. Increased incidence of MCA induced malignancies were found due to the deficiencies in INFγR, STAT1, IL-12, perforin, RAG, and NK cells

A Model of Innate Recognition and Initiation of the Adaptive Anti-tumor Immune Response have the following steps: The tumor invasion starts and inflammatory response occurs. Then the Tumor cells begin expressing "stress" ligands like NKG2D. The cells of the innate system have receptors for NKG2D. Innate cells start inducing apoptosis of tumor cells, which results in production of antigen for APCs like dendritic cells.The tumor cell antigen is presented to T cells by the antigen presenting cells which destroys the tumor.

Vaccines for cancer

In addition to this immunization with tumor Cells have the potential to induce Protective Immune Response. This is evident from the experiments in early '60s, in which mice were inoculated with killed tumor cells.When mice were treated with the same tumor cell, the mice did not develop tumor and the tumor was rejected. After this when the mice was treated with a different tumor, there was growth in tumor.

The idea of tumor specific antigens was introduced after the response obtained from this experiment

Approaches for producing tumor antigen-specific immunity:

There are two approaches for producing or generating tumor antigen specific immunity

The first approach is called a Sloppy approach in which immunization with a whole cancer cell is carried out, but there is a major problem with this method because a lot of other, normal antigens exist on the cell in addition to the cancer antigens. This may result in autoimmunity and can be induced because the immune response is not particularly focused on the tumor antigens.

The second approach is called Better approach as it is better than the sloopy approach. In this approach immunization is done with specific antigens. Thus preventing the problem of autoimmunity, which occurred in the sloopy approach. Eventhough this is considered to be a better approach, it is a complicated process as the specific antigen must be identified

Tumor antigens could be considered as whole proteins or peptides. If the antigens are finalized as peptides, they are easy to produce and can be used as vaccines readily. For preparing the peptides a good knowledge of the MHC scaffolds is required, because the peptides are loaded on MHC scaffolds. The peptides usually are loaded in HLA specific manner due to this reason the peptides that work for one person might not work for other person. So the HLA haplotypes of individual person must be known to administer the vaccine. At present the peptides used as vaccines are designed for patients who are HLA 0201 positive. Particularly this halotype is used because this is a common halotype, 20-25% of people have this HLA gene

Usage of single proteins another hypothetical concern:

If a single protein is used as the antigen and if the protein used is not needed by the tumor, the tumor will lose the protein. When the tumor is susceptible to immunologic response, the selection of resistant variants without the protein will start. If a single protein is used, it must important to the transformation process. This criterion could be fulfilled by a oncogene alone. If the tumor loses the oncogene due to variation, the tumor loses its capability to grow. In this situation the solution of the problem would be to use more antigens, if more antigens are used, the chances of losing them by the tumor cells can be reduced

IMMUNOTHERAPY

Immunotherapy is a new approach in cancer therapy that uses antibodies specifically designed to identify the specific antigens of cancerous cells, In the immunotherapy the specifically designed antibodies are conjugated with natural toxins,drugs or radioactive substances, these conjugated antibodies seek their target cancer cells and destruct them using the toxins they are conjugated with. In an alternate way the toxins can be linked with a lymphokine and directed towards a cell which has a lymphokine receptor

Conclusion and Perspective

From the various experimental studies on the immunity to cancer we can come to a conclusion that though innate and adaptive immunity are significant in their aspects, they interact with each other for the effective immune response, however the mechanism of adaptive immunity is not clear. The theory of immune surveillance and its evidence prove, that there must be a mechanism for immune surveillance to control the tumors

The research on finding suitable therapeutics for cancer like vaccines for cancer and immunotherapy are effective

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