A tumour is a swelling of part of the body caused by abnormal cell growth, this occurs when the normal cell division process becomes unregulated and cells proliferate uncontrolled. This results in cloned cells of the original defective cell, leading to a neoplasm – a new growth of tissue in the body that is abnormal. A tumour at a single site is known as a benign tumour, it becomes malignant (very virulent or infections and prone to reoccurrence after removal) when the tumour cells spreads to further sites within the body and begins to proliferate at these sites. Secondary malignant growths distant from the primary growth are known as metastases.
Not all tumours are cancerous, cancerous cells are damaged cells of the patients body that do not undergo apoptosis (programmed cell death), this means that their growth is no longer controlled and metabolism of the cells are altered.
Malignant tumours are named according to the tissue of origin:
- Carcinoma – Arising in the epithelial tissue of skin or internal organs
- Sarcoma – Arising in connective tissue or other non-epithelial tissue (mesenchymal cells)
- Leukaemia – Arising in haematopoietic cells or blood forming organs such as bone marrow to produce abnormal leukocytes, these also suppress the production of normal blood cells
- Germ Cell Tumours – Arising in reproductive tissues
- Blastoma – Arising in embryonic tissues
- Lymphoma – Arising in the lymph nodes
An early stage malignant tumour is called a premalignant tumour; premalignant tumours and benign tumours can often be treated with surgery alone. With malignant tumours this become much more difficult and other methods must be used in conjunction.
Tumours and the Immune Response
The body has a system in place to attempt to eradicate tumours before they develop, changes to the tumour cells make them a target for the immune system by means such as:
- Macrophage/Dendritic cell – The attack/presentation of an antigen
- CD8 cell mediated cytotoxicity (Cytotoxic T-cells or Tc)
- Natural killer activity (NK cells)
- Antibody dependent cell-mediated cytotoxicity (ADCC)
It is possible that tumours may express abnormal proteins on their surface that could be recognised as foreign antigens, however the immune system normally develops a state of tolerance towards them. This doesn’t occur if the tumour cells enter the lymphoid tissues, where they may activate dendritic cells and antigen processing. This leads to some form of effective anti-tumour immunity – this is more likely to occur when the tumour induces inflammation. This means tumours that do not enter the lymphoid tissue may be ignored by the immune system.
Potential antigen targets on tumours include:
- Tissue specific antigens – Normal proteins which can be found in both normal and cancerous cells
- Reactivated gene products – These are normal proteins but they are not normally expressed after foetal development
- Viral antigens – Foreign proteins which are expressed on cancerous cells as a result of viral infection
- Mutated gene products – These are structurally abnormal proteins
Although tumours express these abnormal antigens, they are not properly presented to the immune system (especially Tc) due to the developed tolerance. However, NK cells, Tc cells and activated macrophages or antibodies may still attack them.
NK Cells and Tumours
NK cells are considered the main defence against tumours. NK cells can rapidly be activated by interferons by cells that have been virally infected; they can also be activated by IL-12 secreted by macrophages. This means NK cells are able to quickly attack abnormal cells, much faster than T or B-cells. One reason tumour cells are a good target for NK cell cytotoxicity is that tumour cells express low levels of MHC class I, the absence/low levels of MHC class I on the tumour cells means that inhibitory receptors on NK cell membranes (KIRs) are not stimulated. Normal cells express large amounts of MHC class I that stimulates the KIRs on the surface of NK cells, this is why normal cells are not targeted. NK cells kill cells expressing low levels of MHC class I by releasing cytolytic agents into the target cell (like cytotoxic T-cells). It is possible for multiple NK cells to attach and lyse a single tumour cell.
IL-2 and IFNg stimulate NK cell growth and make them more cytotoxic. Activated macrophages secrete IL-12 and TNF; these stimulate NK cells to produce IFNg that causes the activation of more NK cells activating further macrophages – Positive feedback. It is for this reason IFNg is proposed as a means of anti-tumour therapy.
NK cells can also kill by ADCC (antigen dependent cell-mediated cytotoxicity). This is where an antibody will bind to an antigen on the target tumour cell. An Fc receptor on the NK cell will then bind to the Fc portion of the antibody linking the NK cell to the tumour cell. The NK cell will then secrete its cytolytic agents into the tumour cell, resulting in lysis.
Macrophage and Antibody-Mediated Immunity to Tumours
Macrophages are activated by IFNg generated by tumour cells. The activated macrophages are directly cytotoxic. By increasing their production of IL-1 and TNF they are able to activate T-Helper cells and NK cells. It is possible however for some tumours to inhibit macrophage activation.
Antibodies are present mainly in animals with lymphosarcomas. It is possible that alongside complement they can lyse free tumour cells but not cells in solid tumours.
Failure of Immune Response to Tumours
Immunosuppression is the most common cause of tumours (although tumours can be present in organisms with fully functional immune systems) and results typically in lymphoid tissue tumours. It is possible for tumours to secrete products that subvert immune responses. E.g. the secretion of IL-4, 6, 10 and TGF will deactivate macrophages and suppress T-helper 1 responses. Tumours can also activate suppressor regulatory T-cells or macrophages.
- Active – Using stimulants (most common is BCG) to directly activate macrophages stimulating cytokine release.
- Passive Cytokine Therapy– IFNs can be used, but have limited success. Cytokines can prove highly toxic and are therefore not often used and have limited success anyway.
- Activated Cytotoxic Cell Therapy – Lymphocytes are taken from a tumour bearing organism and incubated in-vitro with IL-2. They are then returned to the patient where they are more cytotoxic.
- Antibody therapy (Serotherapy) – This can prove successful against some forms of viral tumours. The antibodies reduce the virus load and can attack infected cells too.
- Monoclonal antibody therapy – Antibodies specific to the tumour are conjugated to a toxin or radioactive molecule. The binding of the antibody to the tumour cell causes the toxin to be internalised and kill the cell or in the case of the radioactive molecule, the radiation kills the tumour cell.
- Dendritic Cell Therapy – A tumour cell is linked to a cytokine that binds to a dendritic cell precursor. The precursor cell takes in the complex and the dendritic cell matures. The mature dendritic cell is infused back into the patient where it displays the tumour antigen and activates T-cells. The T-cells then attack the tumour cell.
- Anti-Tumour Vaccines – Killed tumour cells or purified tumour antigens are used as vaccines to stimulate the immune system. DNA vaccines or dendritic cell vaccines can also be used. Anti-viral vaccines are the most effective.