A cancerous tumour - A mass of cells showing uncontrolled growth, with a tendency to invade and damage surrounding tissues. The tumour cells have the ability to spread to other parts of the body, sending daughter growths to sites remote from the primary growth.
Cancer occurs when the DNA sequence within a gene is mutated. The mutation may be caused by exposure to drugs, chemicals or radiation. The gene can no longer instruct the cell in which it resides to produce the normal version of the protein it encodes. When DNA mutation occurs two genes are affected:
Proto-oncogenes become Oncogenes:
· Pronto-oncogenes are normal genes that promote progression through the cell cycle. Normally at the end of the stimulatory pathway, these genes code for growth factors that stimulate active cell division. They are only stimulated when cell division is necessary. For example after an injury.
· Mutations in the proto-oncogenes cause them to become oncogenes (cancer causing genes). Oncogenes are under constant stimulation and keeping promoting cell division regardless of the circumstances. Resulting in uncontrolled cell division.
Tumour Suppressor Genes become inactive:
· Normally these genes code of a signal protein in the inhibitory pathway. These genes can either promote apoptosis, or prevent the progression of the cell cycle when DNA is damaged.
· When the Tumour Suppressor Genes are inactivated, uncontrolled cell division takes place. Resulting in tumour development.
Every cell in the human body has the potential to become cancerous, if the growth restraints placed on normal cells is altered. The DNA changes that occur will be passed on to all daughter cells that arise from the original cancer cell. This results in abnormal cell accumulations forming a tumour. The cancerous cells are pushed out of their boundaries, and infiltrate normal tissue. Clumps of the tumour may become dislodged and migrate to a secondary site through either the blood or lymph fluids.
A cell containing mutated genes (DNA), which result in the loss of its growth control, is referred to as a transformed cell. It is however important to note that mutations of our DNA are constantly happening due to environmental insults. A single DNA mutation will not result in cancer. Multiple mutations are required for a transformed cell to become cancerous.
The complex and paradoxical relationship between The Immune system and Malignancy
In 1909, scientist Paul Ehrlich, proposed the general concept that the immune system plays a role in the identification and elimination of transformed cells. He theorized that the incidents of cancer would be much higher if it were not for the interventions of our own immune system.
50 years later, Lewis Thomas and Frank MacFarlane Burnet, expanded on Ehrlich's theory, introducing the T-Cell, and tumour antigens. The T-Cell was of central importance in the immune systems response to cancer cells. The concept of "immunosurveillance" was introduced. The idea that the immune system is on constant alert against transformed cells.
The theory of "immunosurveillance" remained controversial, until 2001, when Robert D. Schreiber and colleagues, presented evidence that showed the immune system is capable of preventing tumours from developing, and therefore has a protective role against cancer. The research also uncovered new insights into the immune system and the mechanism of tumour development, that they called "cancer immunoediting".
The research that has emerged over the past four decades, shows a relationship between the immune system and cancer. It has come to light that the immune system plays a dual role in the prevention and the promotion of tumour development. Some cancer cells are actually protected by our own immune system.
Immunosurveillance
The theory of immunosurveillance, is that the body's own immune system recognizes cancer cells as being "atypical" as soon as they are produced, and destroys them immediately. Only when these transformed cells are not recognized by the immune system, and evade being destroyed, do they develop into tumours and cancer.
However a research team from the "Laboratoire Immunologie - Immunopathologies - Immunotherapies" in France, has proved that the immune system actually does not eradicate these potential cancer causing cells, but rather protects them as it would any other normal body cell. Transformed cells did not possess the appropriate "danger signals" needed to trigger the immune response.
When an immune response is triggered, the immune system produces lymphocytes to fight and eradicate the invading pathogen and/or abnormal cell.
Regulatory T-Cells: recognize the bodies normal cells and protect tissues from being attacked. Activated at all times to protect healthy tissues. They are mobilized rapidly.
Effector T-Cells: recognize abnormal cells, and foreign components, their purpose is to attack and destroy.
In the very first few days after the appearance of the tumour cells, it has been shown that the transformed cells induce an immediate response from the Regulatory T-Cells, which migrate rapidly to the site of the tumour development. They recognize membrane plasma proteins on the surface of the transformed cell as being normal. Proteins that are expressed by normal body tissues. The Regulatory T-Cells therefore protect these transformed cells as if they were normal body cells. The Regulatory T-Cells block the possible attack by the Effector T-Cells, thereby preventing them from attacking and destroying the transformed cells. In essence, the Regulatory T-Cells are the first to discover the potential tumor and facilitate its growth, by preventing its eradication by the Effector T-Cells.
The scientists have proved that if the Regulatory T-Cells were absent, and not the first encounter between the transformed cells and the immune system, the Effector T-Cells would indeed destroy and eradicate any potential tumour from forming. This research suggests that for the effective treatment of future cancer development, the Regulatory T-Cells response needs to be controlled so that the Effector T-Cells are able to destroy the transformed cells, to prevent tumour development.
Cancer Immunoediting
How can dormant cancerous tumor survive even though an immune response has been provoked?
The cancer immunoediting model is aimed at answering the age old question as to how and why tumours can lie dormant in patients for years and years before re-emerging. The model also provides a new platform for improved cancer treatments, and protocols that are aimed to interfere with the processes that contribute to tumour growth and development.
The immune system has a dual effect on the progression and prevention of cancer. It can prevent and suppress tumour growth by destroying cancer cells, but also promotes tumour progression by protecting the tumour cells that are capable of surviving in an immunocompetent host. Immunoediting is a conceptual framework which integrates the immune system's role in both tumour destruction and promotion. The basis of the cancer immunoediting hypothesis, is that the immune system controls the tumour quantity and quality (immunogenicity). Preventing tumour formation, yet at the same time allowing for the shaping the tumour quality.
The immune system has at least three distinctive roles in the prevention on tumour development:
It protects the host from viral infection, thereby suppressing virus induced tumors.
It prevents the establishment of an inflammatory environment (inflammation can promote tumourigenesis)
It eliminates tumour cells in certain tissues. It has been discovered that the transformed cell does actually produce a tumour antigen, and does not just over express natural body antigens. Therefore newly developed transformed cells display antigens that are recognized by the lymphocytes of an adaptive immune system and are not subject to immunological tolerance.
The cancer immunoediting process, proceeds through three distinct and sequential phases. "Elimination, Equilibrium, Escape." However some tumours may enter the cycle at Equilibrium or Escape, without passing through a prior phase. External environmental factors may influence the directionality of progression.
Elimination - Equilibrium - Escape
Elimination:
The innate and adaptive immune systems work in unison to detect and destroy a developing tumour. The two systems work together in a modified version of immunosurveillance, to eradicate a potential tumour before it is clinically detected. The immune system is able to recognize and attack the tumour cells that are clearly abnormal. Cell abnormalities may include the display of foreign antigens, the secretion of cytokines related to dysfunctional cells, or cell behavior that the immune system recognizes as being dangerous.
There is evidence that the innate immune system can protect against tumour development on its own, however in most cases immunosurveillance responses are better if there is expression of tumour antigens on the tumour cells that activate the Effector T-cells. A balance between innate and adaptive immunity is required to protect the host from potential tumour development.
If the tumour cells and potentially cancerous tumour are destroyed completely during the Elimination phase, this is the end point of the cancer immunoediting process.
Equilibrium:
Rare tumour cells that have survived the elimination phase, enter the equilibrium phase. The tumour cells continue to divide rapidly. The immune system prevents tumour outgrowth, but sculpts the quality of the tumour cells. The tumour cells accumulate mutational changes either by chance or in response to pressures placed on them by the immune system itself. These mutations and pressures that have been accumulated over time, enable the tumour to impair the immune systems ability to destroy them.
A balance between tumour growth and immune control is established. The equilibrium phase is the longest stage of the cancer immunoediting process. During this phase, the residual tumour cells are held in a functional state of dormancy. Equilibrium represents a phase where the outgrowth of tumour cells is controlled by the immune system.
Over time, the eventual entry of the tumour cell into the final stage of the immunoediting process, is caused by the continued sculpting of these cells by the immune system.
Escape:
The final stage of the cancer immunoediting process. Tumour cells that have survived recognition and elimination of the immune system, grow as visible tumours. The progression from equilibrium to escape can be brought on by the changes that have occurred in the tumour cells as a response editing by the immune system, and/or because the immune system itself has become compromised or has increased cancer-induced immunosuppression.
Alterations at the tumour cell level, lead to reduced recognition on the tumour cells by the immune system, or tumour cell resistance to the cytotoxic effects of the immune system. All of which lead to tumour growth and development. The best known escape method, is the tumour cells loss of tumour antigen expression. The cancer cell thereby becomes "invisible" to the immune system, and acquire the ability to grow progressively . The loss of antigen can occur in three ways, all of which are speculated to be caused by a genetic instability within the tumour cell:
1. The emergence of tumour cells that lack the expression of rejection antigens.
2. The loss of MHC Class I proteins, that present antigens to T-Cells.
3. The loss of antigen processing functions inside the cell itself.
When the establishment of an immunosuppressive state within the tumour microenvironment is achieved, the cancer cells may also escape detection. The tumour cells can promote the development of the immunosuppressive state by releasing immunosuppressive cytokines and/or by the recruitment of Regulatory T-Cells that function as immunosuppressors. The tumour cells thus shuts down the normal immune response that would ordinarily recognize and control tumour growth.
The effects on Immunotherapy & future cancer treatment
Although most studies with regards to the cancer immunoediting hypothesis have been conducted with mice, recent evidence shows that immunoediting does occur in humans. It can change the developmental course of tumours in cancer patients.
Due to the discovery of how tumour cells escape and evade the immune system, more effective immunotherapy treatments are be developed. Effective cancer immunotherapies will need to have increased quality and quantity of immune cells that have the ability to detect and destroy the tumour cells, seek out and reveal additional protective tumour antigens, and eliminate cancer induced immunosuppressive states.
Immunological approaches towards the treatment and control of cancer are now being established. The advances that have been made in defining the cancer antigen and understanding the role of immunosuppression in the development of cancer, have paved the way for an new era of cancer therapy. Therapy that focuses on the strength and specificity of our own immune system.
