Essay on Tumour!
1. Introduction:
A tumour (L. tumere = to swell) is a growth or lump of tissue resulting from neoplasia or abnormal new cell growth and reproduction due to the loss of normal growth-control mechanisms. There are two major types of tumours, benign and malignant, with respect to overall form or growth pattern.
A tumour that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is called benign, whereas a tumour that continues to grow and becomes progressively invasive is referred to as malignant; the term cancer refers specifically to a malignant tumour.
Malignant or cancerous tumour cells can actively spread throughout the body in a process known as metastasis. Metastasis is a process in which small clusters of cancerous cells dislodge from a tumour, invade the blood or lymphatic vessels, and are carried to other tissues where they continue to proliferate establishing secondary tumours. Malignant tumours or cancers are classified according to the embryonic origin of the tissue from which the tumour is derived.
Most malignant tumours or cancers are carcinomas, the tumours which develop from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. The majority of cancers of the colon, breast, prostrate, and lung are carcinomas. Other malignant tumours or cancers are leukemias, lymphomas, and sarcomas.
The leukomas and lymphomas are the malignant tumours or cancers of hematopoietic cells of the bone marrow; these tumours are not solid like carcinomas, but cell suspensions. Leukemias proliferate as single cells, whereas lymphomas tend to grow cell masses. Sarcomas are derived from mesodermal connective tissues (e.g. bone, fat, cartilage) and arise less frequently.
2. Tumour Antigens:
Two types of antigens express on tumour cells:
(i) Tumour-specific antigens (TSAs) and
(ii) Tumour-associated transplantation antigens (TATAs).
(i) Tumour-specific antigens (TSAs):
Tumour-specific antigens (TSAs) are unique to tumour cells and do not occur on normal cells in the body. These antigens may result from mutations in tumour cells that generate altered cellular proteins. Cytosolic processing of these proteins gives rise to novel peptides that are presented with class I MHC molecules.
Virus induced tumour cells may express virus specific antigens with a cross- reactivity specificity in all tumours induced by the same virus. For convenience, the common oncogenic RNA virus causes T-cell leukemia in man where viral antigen activates cellular oncogenes to transform cell into a malignant one.
There are some tumours which are induced by chemical carcinogens (e.g., methylcholanthrene, azodyes). These chemically induced tumours have distinct tumour-specific antigens characteristic of that chemical, and do not show any cros-reactive pattern as in case of virally induced tumours.
(ii) Tumour-associated transplantation antigens (TATAs):
Tumour-associated transplantation antigens (TATAs). are proteins and are not unique to tumour cells. They are expressed both on normal and tumour cells but to a much greater extent on tumour cells. The best studied tumour-associated transplantation antigens are the oncofoetal antigens which are normally associated with embryogenesis.
These antigens are expressed on normal cells during embryonic development when the immune system is immature and unable to respond but that normally are not expressed in adults. Reactivation of embryonic genes that encode these proteins in tumour cells results in their expression on the fully differentiated tumour cells.
Most commonly studied oncofoetal antigen is carcino embryonic antigen (CEA) which is a faulty glycosylated protein appearing on the foetal gut and cancer cells found on the human colon. However, tumour-associated transplantation antigens (TATAs) are capable of inducing graft-rejection reactions in syngeneic hosts.
3. Tumour Evasion of the Immune System:
Although the immune system of the body clearly can respond to malignant tumour cells (cancerous cells) and destroy them, the fact that a large number of individuals become the victims of cancer every year and finally die suggests that the immune response to tumour cells is often ineffective.
The tumour cells, with the help of certain mechanisms, appear to evade the immune system of the body and cause death of the individual.
Some important mechanisms of tumour evasion of immune system are the following:
(i) Serum blocking factors:
Experimental search was conducted about three decades ago to test the ability of serum (taken from tumour bearing individuals) to block tumour cell killing by lymphocytes of the immune system.
The result demonstrated was that the serum from tumour bearing individuals (animals as well as humans) do contains certain ‘blocking factors’ that can abrogate killing of the target tumour cells by lymphocytes immune to their specific antigens. These blocking factors are, most probably, the complexes formed between the antigens released from the tumours and antibodies formed by the host.
(ii) Antitumour antibody as a blocking factor:
Antitumour antibodies itself function as a blocking factor in certain cases. It is considered that the antitumour antibody binds to tumour specific antigens and masks the antigens from cytotoxic T-cells.
In other cases, the antitumour antibodies do not act alone as blocking factor but rather they bind to tumour antigens forming antigen-antibody complexes that act as blocking factors and block the cytotoxic T-lymphocyte response. These complexes also may inhibit antibody-dependent cell- mediated cytotoxicity (ADCC) by binding to Fc receptors or natural killer cells (NK cells) or macrophages and blocking their activity.
(iii) Antigenic modulation:
It has been observed that certain tumour specific antigens (TSAs) disappear from the surface of tumour cells in presence of serum antibody and reappear after the serum antibody is no longer present. This phenomenon is called antigenic modulation. The antigenic modulation is readily demonstrated when leukemic T-cells are injected into mice previously immunized with a leukemic T-cell antigen (TL antigen).
The injected mice develop high titers of anti-TL antibody which binds to the TL antigen on the leukemic cells and induces capping, endocytosis, and/or shedding of the antigen-antibody complex.
As long as the antibody is present, these leukemic T-cells do not display the TL antigen and thus can not be eliminated. It is concluded therefore that as long as the antibody is present it tends to acquire blocking action and protects the target against cell-mediated host defence.
(iv) Immunosuppressive secretions:
Some tumour cells may secrete immunosuppressive compounds, which inhibit the activity of nearby immune cells. This immunosuppressive activity is exhibited by alpha fetoprotein secreted by tumour cells and prostaglandins released by macrophages of tumour-bearing hosts.
(v) Low level expression of class I MHC molecules:
A number of tumours have been demonstrated to express every low levels of class I MHC molecules on the surface of their cells. This low level expression of class I MHC molecules can be accompanied by progressive tumour growth because CD8+ cytotoxic T-lymphocytes (CD8+ CTLs) recognize only class I MHC molecule as antigens and any alteration in the expression of these antigens on tumour cells exerts a profound effect on the cytotoxic T-lymphocyte (CTL) mediated immune response.
(vi) Poor co-stimulatory signals:
For immune response, T-cells require to be activated involving an activating signal and a co-stimulatory signal. Both signals are needed to induce interleukin-2 (IL-2) production and T-cell proliferation.
The poor immunogenicity of many tumour cells may be due in large part to lack the co-stimulatory signals provided by antigen-presenting cells (APCs). Since the APCs are very poor in number in the immediate vicinity of a tumour, the T-cells will receive only a partial activating signal, which may lead to clonal anergy.
In addition to the above mentioned, certain other mechanisms, for example, immunosuppression brought about by X-irradiation, immunosuppressive drugs, immunological tolerance, or the natural decline in immune reactivity with old age may be involved in tumour evasion of the immune system.
4. Tumour Immunotherapy:
Since it was recognized that many tumour cells do evade an immune response and make large number of individuals victims of cancer each year, much effort has been made to make immunotherapy a successful approach to treat cancer. One such immunotherapic approach to treat cancer is to augment or supplement the natural defence mechanisms of the body.
Several types of immunotherapic devices to treat cancer are in current use or under development; some important ones are the following:
(i) Monoclonal antibody-polypeptide conjugate treatment:
Monoclonal antibodies specific to a cell-type yield a conjugate molecule called immunotoxin when linked with a toxin polypeptide. The antibody component of immunotoxin ensures its binding specifically and only to the target cells, and the attached toxin kills such cells.
This approach has been used to kill tumour cells in which the monoclonal antibodies specific to tumour cells have been linked to Ricin A, the toxic polypeptide of the natural toxin ‘Ricin’ found in the endosperms of castor (Ricinus communis), to obtain antibody-Ricin A conjugate (the immunotoxin).
The antibody-Ricin A conjugate has been shown to kill target tumour cells by inhibiting protein synthesis in them. In fact, the antibody used in the conjugate binds specifically to the antigen molecules present on the surface of target tumour cells, and the Ricin A polypeptide enzymatically and irreversibly modifies the larger subunit of ribosomes (actually their EF2 binding site) making them incapable of protein synthesis. It is noteworthy that the antibody-Ricin A conjugate (the immunotoxin) docs not bind to either other tumour cells or the normal cells.
(ii) Monoclonal antibody treatment:
Monoclonal antibodies have been used in various ways as experimental immunotherapeutic agents for cancer.
Some such experimental achievements are the following:
(i) Anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. But, this approach requires that a custom monoclonal antibody be raised for each lymphoma patient. This is prohibitively expensive and cannot be used as a general therapeutic approach for the thousands of patients diagnosed each year with B-cell lymphoma.
(ii) A more general approach of monoclonal antibody therapy for B-cell lymphoma is demonstrated recently. Most B-cells, whether normal or cancerous, bear CD20 antigens. When a monoclonal antibody (raised in mice and engineered to contain mostly human sequences) binds to this antigen, the result is the treatment of B-cell lymphoma to a considerable extent. Aside from CD20, a number of tumour-associated antigens are being tested in clinical trials for their suitability as targets for monoclonal antibody-mediated anti-tumour therapy.
(iii) Cytokine therapy:
Various cytokines are produced at large-scale by way of gene cloning. A number of experimental and clinical approaches have been developed to use these recombinant cytokines, cither singly or in combination, to augment the immune response against cancer.
The cytokines that have shown useful in cancer immunotherapy are interferon-α, β and γ; interleukin-1, 2, 4, 5, and 12; and TNF. However, this immunotherapeutic approach to treat cancer is still in its infancy because though the cytokines have produced occasional encouraging results in clinical trials, a number of obstacles still remain to be solved for successful use of cytokines to treat cancer.
(iv) Vaccination:
Vaccination is another approach to counter cancer. Chickens have been protected from Merek’s lymphoma by vaccination. Mice has been vaccinated against malignant melanoma. In this case the normal mice were first vaccinated (immunized) with irritated melanoma cells and then challenged with unaltered malingnant melanoma cells.
The ‘vaccine’ was found to protect a high percentage of the mice. It is hoped from these experimental results that a similar vaccine might prevent metastasis after surgical removal of primary melanoma in human patients.
(v) Mutagenic drugs:
Treatment of cancer cells with mutagenic drugs leads to expression of new (and hopefully strong) antigenic determinants on cancer cells which can mount a powerful immunological response against cancer cells.