In this article we will discuss about:- 1. Meaning of Neoplasms 2. Growth Characteristics of Neoplasms 3. Cellular Basis 4. Benign and Malignant 5. Classification 6. Host Responses.
Meaning of Neoplasms:
Neoplasia, literally meaning ‘new growth’, is a disorder characterized by the abnormal and continuous growth of cells which are no longer subject to the homeostatic controls which maintain the appropriate number of cells in normal tissues. In most cases these cells form a solid mass of tissue which is referred to as a tumour (literally ‘swelling’) or neoplasm.
An exception to this is leukaemia in which the abnormal cells arise from precursor cells in the bone marrow and pass into the bloodstream in the same way as normal blood cells.
Growth Characteristics of Neoplasms:
Under normal circumstances the number of cells in a given tissue is subject to variation. Thus, when an increased workload demand is placed upon a particular tissue, the tissue may respond by increasing cell number, a process known as hyperplasia. In some settings hyperplasia may be abnormal.
Cells which no longer have the capacity to divide respond to increases in workload demand by increasing cell size. This is known as hypertrophy. Examples of hypertrophy include the increase in skeletal muscle size in training atheletes and the ‘pathological’ hypertrophy of the muscle cells of the left ventricle (left ventricular hypertrophy) that occurs in long-standing hypertension.
In contrast to the process of hyperplasia and hypertrophy which are essentially reversible once the provoking stimulus has been removed, neoplastic growth is usually not reversible. Neoplastic cells are no longer responsive to the controlling mechanisms that maintain cell number in normal tissues and therefore continue to divide under circumstances in which normal cells cease proliferation.
The net result is the progressive accumulation of neoplastic cells and the formation of a tumour mass. The differences in growth regulation between normal and neoplastic cells may be summarized under the following five headings.
i. Growth Factor Dependency:
Stimulation of a normal cell into a proliferative state often depends upon an external signal in the form of a growth factor. Platelet-derived growth factor (PDGF) is an example of a growth factor. Following tissue damage, PDGF is released by platelets and stimulates adjacent fibroblasts to divide and form a fibrous scar.
Many growth factors bind to receptors situated on the surface of target cells. Binding of growth factor to a receptor initiates a series of biochemical changes within the cell which ultimately leads to cell division.
Tumour cells are not as dependent on growth factors as normal cells and are able to proliferate when concentrations of growth factors are much lower than those required by normal cells. These differences in growth factor requirements can be explained by several possible mechanisms.
Tumour cells may secrete growth factors which are able to stimulate their own proliferation (autocrine stimulation), or they may respond more vigorously to growth factors produced by other cells. Alternatively, the tumour cells may proliferate in the absence of the usual growth factors required by normal cells.
ii. Density-Dependent Inhibition of Growth:
Once normal dividing cells reach a finite density they stop proliferating. In contrast, neoplastic cells do not cease proliferation but continue to replicate to much higher densities than normal cells.
iii. Anchorage Dependence:
Most normal cells need contact with a substratum in the extracellular environment to reproduce. Neoplastic cells, on the other hand, are able to grow without attachment to a substratum. This is well illustrated in vitro by the ability of tumour cells to form colonies when suspended as single cells in agar.
iv. Contact Inhibition of Movement:
When normal cells are placed in culture, they have the ability to respond to the presence of other cells. Thus, when two cells come into contact, one or both will change direction ensuring that the cells do not overlay each other. This characteristic is referred to as contact inhibition of movement. Neoplastic cells lack contact inhibition of movement and often grow over or under each other.
Tumour cells are less adhesive than normal cells and are less firmly attached to neighbouring cells or the extracellular matrix. Loss of adhesiveness contributes to the invasive and metastatic properties of some neoplasms.
The Cellular Basis of Neoplasms:
Neoplasms are believed to arise from a single target cell which has undergone a series of genetic changes (mutations) that ultimately result in its ability to escape the normal proliferative controls imposed upon normal cells. Mutations may occur spontaneously within cells or they may be induced following exposure to chemicals or radiation. Most mutations impair cell survival and ultimately result in cell death.
However, in some cases a mutation may provide a cell with a growth advantage when compared to its normal counterparts. Mutations that enhance cell growth usually arise either in genes that stimulate cell division (oncogenes), or in those that inhibit cell division (tumour suppressor genes).
A cell bearing a beneficial mutation may continue to divide until a collection of genetically identical cells or clone is formed. Cells from this clone may in turn acquire new mutations which further enhance their growth potential. Eventually a point may be reached when some of these cells are able to grow in an uncontrolled fashion and a tumour results.
Once a tumour is established, mutations within tumour cells may give rise to multiple sub-clones within the tumour, each with differing properties. This is referred to as tumour heterogeneity and is an important concept in relation to tumour progression.
Benign and Malignant Neoplasms:
Neoplasms are broadly divisible into benign and malignant subgroups. Cancer is a term which is commonly used to describe the disease which results from the presence of a malignant neoplasm.
Benign and malignant neoplasms differ in a number of important ways as given below:
i. Invasion and Metastasis:
Malignant neoplasms are characterized by their capacity to invade surrounding normal tissue and to spread to distant parts of the body to generate secondary growths. This latter property is known as metastasis. In general, benign tumours do not invade adjacent tissues and do not metastasize.
ii. Degree of Differentiation:
The tumour cells of benign neoplasms closely resemble the cell origin and are therefore described as being well differentiated. Although malignant neoplasms may also be well differentiated, many are either poorly differentiated (Cells of the tumour do not closely resemble cell of origin) or undifferentiated (the origin of tumour cells cannot be determined). In general, undifferentiated tumours have higher growth rates than their well differentiated counterparts.
iii. Clinical Outcome:
Malignant neoplasms are often fatal to their host. This is primarily due to their ability to metastasize and to develop resistance to various forms of therapy. In contrast, benign neoplasms are life-threatening only in the following exceptional circumstances.
If the tumour is present within, or impinges upon, a vital structure. Certain benign tumours of the atrium (atrial myxomas) may cause valve obstruction, cardiac insufficiency and sudden death in some cases.
If the tumour produces a physiologically active substance in increased amounts. Some benign tumours of the adrenal medulla (phaeochromocytomas) secrete excessive amounts of adrenaline leading to hypertension which can precipitate myocardial infarction or cerebral haemorrhage. Likewise, beta-cell adenomas of the pancreas can secrete enough insulin to produce fatal hypoglycaemia (low blood glucose levels).
If the tumour is present within the central nervous system (CNS). Because the CNS is an enclosed system, expanding lesions can cause pressure damage to surrounding nervous tissue or produce more serious complications as a result of associated rises in intracranial pressure.
Classification of Neoplasms:
Neoplasms are usually classified on the basis of the presumed cell or tissue of origin irrespective of the site at which the tumour is found. Thus, squamous cell carcinomas are malignant neoplasms derived from squamous epithelial cells. Since this type of epithelial cell is found in many locations within the body, squamous cell carcinoma can arise in many sites which include skin, oesophagus and cervix.
Some neoplasms, for example chronic myeloid leukaemia (CML) arise in stem cells. Stem cells are present in small numbers in cell populations and have two critical functions: to generate descendants which will become differentiated and perform the function of the tissue; and to renew themselves so that a stable number of stem cells remain.
CML is characterized by the accumulation of neoplastic cells of differing myeloid lineages which have all descended from a common neoplastic myeloid stem cell.
Host Responses to Neoplasms:
The concept of immune surveillance suggests that the immune system is able to eradicate potential cancer cells and that cancer arises because of a defect in this surveillance process. This is supported by the observation that cancer is more common in immunosuppressed individuals.
However, only certain cancers occur with increased frequency in immunosuppression, particularly lymphomas and leukaemias, and the incidence of the more common cancers, such as lung and breast, is not significantly increased.
Host defence systems include both adaptive and innate systems. The adaptive arm of the immune system includes antigen-specific T and B lymphocytes which have the capacity of distinguishing self from non-self. It follows that if tumours are to be recognized by T or B lymphocytes they must express non-self-antigens.
Non-self-antigens found on tumour cells are referred to as tumour antigens. Experimental cancers induced in laboratory animals either by chemicals, radiation or viruses frequently express antigens which are not found on normal cells and which are often unique to individual tumours. These tumour antigens are known as tumour specific antigens. In contrast, spontaneous tumours in animals are weakly, if at all, immunogenic.
The majority of antigens present on human cancers are not unique to tumour cells but are also present on normal cells and are called tumour-associated antigens. These antigens may be normally expressed only on fetal cells and not on adult cells, or they may be expressed at low levels on tumour cells. An example of a tumour-associated antigen is a protein designated p97 which is found at high levels on melanoma cells.
A vaccine has been developed against this protein which has been shown to protect mice from developing malignant melanoma. Results such as this highlight the potential use of tumour-associated antigens as targets for therapeutic intervention in some forms of cancer.
Immune responses to tumour antigens may be mediated by a number of integrated and interdependent cell systems as described in the following sections:
i. B Cells:
For antibodies to have an anti-tumour effect, the tumour must express an antigen recognizable to B cells. In most cases the antigen must also be recognized by T helper cells that are capable of secreting lymphokines including the interleukins IL-4, IL-5, and IL-6 which are necessary for B cell proliferation and differentiation. Once antibody has bound to the target cell it may induce antibody-dependent cellular cytotoxicity (ADCC), or complement-mediated lysis.
ii. T Cells:
Cytotoxic T cells recognize antigen in association with MHC Class I molecules and are important in the recognition and elimination of virus-infected tumour cells. T cell secretion of interferon-gamma (IFN-γ) activates macrophages and increases expression of MHC molecules on tumour cells.
The precise role of T cells, however, is unclear since some T cell depletion syndromes, for example athymic mice and Di George’s syndrome in humans, do not show a significant increase in spontaneous malignancies.
iii. Natural Killer Cells:
Natural killer (NK) cells are a distinct lymphocytic lineage as illustrated by patients with severe combined immunodeficiency (SCID) who have no B or T cells but do have NK cells. The importance of NK cells in tumour immunity is highlighted in the beige mouse strain and in Chediak-Higashi syndrome in humans. In both cases there is a marked impairment of NK function and an increase in the incidence of certain types of cancer.
Although it is not known how NK cells recognize tumour cells, recognition does not require processing or presentation and is not MHC-restricted. NK cells possess neither surface immunoglobulin nor T cell receptors. However, NK cells do have Fc receptors and can participate in ADCC.
Activated macrophages also have Fc receptors and can participate in ADCC. They can also induce tumour cell lysis by the release of a variety extracellular factors which include tumour necrosis factor-alpha (TNF-α).