Cancer is caused by generic change in a single cell resulting in its uncontrolled multiplication.
Thus, tumours are monoclonal. Two types of regulatory genes- oncogenes and antioncongenes are involved in the development of cancer (carcinogenesis). In recent years, a third category of genes that control the cell death or apoptosis are also believed to be involved in carcinogenesis.
The genes capable of causing cancer are known as were originally discovered in tumor causing viruses. These viral oncogenes were found to be closely similar to certain genes present in the normal host cells which are referred to as protogenes. Now, about 40 viral and cellular protoncogenes. Now, about 40 viral and cellular protogenes have been identifies. Protooncogenes encode for growth-regulating proteins. The activation of protooncogenes to oncogenes is an important step in the causation of cancer.
ACTIVATION OF PROTOONCOGENES TO ONCOGENES
There are several mechanisms for converting the protooncogenes to oncogenes; some of the important ones are described hereunder.
1 Viral insertion into chromosome: When certain retroviruses (genetic material RNA) infect cells, a complementary DNA (cDNA) is made from their RNA by the enzyme reverse transcriptase. The cDNA so produced gets inserted into the host genome. The integrated double-stranded cDNA is referred to as provirus. This pro-viral DNA takes over the control of the transcription of cellular chromosomal DNA and transforms the cells. Activation of protooncogene myc to oncogene by viral insertion ultimately causing carcinogenesis is well known. Some DNA viruses also get inserted into the host chromosome and activate the protooncogenes.
2. Chromosomal translocation: Some of the tumours exhibit chromosomal abnormalities. This is due to the rearrangement of genetic material (DNA) by chromosomal translocation i.e. splitting off a small fragment of chromosome which is joined to another chromosome. Chromosomal translocation usually results in over expression of protooncogenes.
Burkitt's lymphoma, a cancer of human B-Lymphocytes, is a good example of chromosomal translocation. In this case, a fragment from chromosome 8 is split off and joined to chromosome 14 containing myc gene. This results in the activation of inactive myc gene leading to the increased synthesis of certain proteins which make the cell malignant.
3. Gene amplification: Several fold amplifications of certain DNA sequences are observed in some cancers. Administration of anticancer drugs methotrxate (an inhibitor of the enzyme dihydrfolate reductase) is associated with gene amplification. The drug becomes inactive due to gene amplification resulting in a several fold (about 400) increase in the activity of dihydrofolate reductase.
4. Point mutation: The ras protooncogene is the best example of activation by point mutation (change in a single base in the DNA). The mutated ras oncogene produces a protein (GTPase) which differs in structure by a single amino acid. This alteration diminishes the activity of GTPase, a key enzyme involved in the control of cell growth (details described later).
The presence e of ras mutations is detected in several human tumors-90% of lung. However ras mutations have not been detected in the breast cancer.
MECHANISM OF ACTION OF ONCOGENES
Oncogenes encode for certain proteins, namely oncoproteins. These proteins are the altered versions of their normal counterparts and are involved in the transformation and multiplication of cells. Some of the products of oncogenes are discussed below.
Growth factors: Several growth factors stimulating the proliferation of normal cells are known. They regulate cell division by transmitting the message across the plasma membrane to the interior of the cell (transmembrane signal transduction). It is believed that growth factors play a key role in carcinogenesis.
The cell proliferation is stimulated by growth factors. In general, a growth factor binds to a protein receptor on the plasma membrane. This binding activates cytoplasmic protein kinases leading to the phosphorylation of intracellular target proteins. The phosphorylated proteins, in turn, act as intracellular messengers to stimulate cell division, the mechanism of which is not clearly known.
Transforming growth factor (TGT-α) I a protein synthesized and required for the growth of epithelial cells. TGT-α is produced in high concentration in individuals suffering from psoriasis, a disease charter zed by excessive proliferation of epidermal cells.
Growth factor receptors: Some oncogenes encoding growth factor receptors have been identified. Over expression and/or structural alternations in growth factor receptors are associated with carcinogenesis. For instance, the over expression of gene erb-B, encoding EGT-receptor is observed In lung cancer.
GTP-binding proteins: These are a group of signal traducing proteins. Guanosine triphosphate (GT)- binding proteins are found in about 30% of human cancers. The mutation of ras protoongene is the single-most dominant cause of many human tumors.
The involvement of ras protein (product of ras gene) with a molecular weight 21,000(P21) in cell multiplication. The inactive ras is in a bound state with GDP. When the cells are stimulated by growth factors, ras P21 gets activated by exchanging GDP for GTP. This exchange process is catalyzed by genuine nucleotide releasing factor (GRF). The active ras P21 stimulates regulators such as cytoplasmic kinases, ultimately causing DNA replication and cell division. In normal cells, the activity of ras P21 is short lived. The GTPase activity, which is an integral part (intrinsic) of ras P21, hydrolyses GTP to GDP, reverting ras 21 to the original state. There are certain proteins, namely GTPase activating proteins (GAP), which accelerate the hydrolysis of GTP of ras P21. Thus in normal cells, the activity of ras P21 are well regulated.
Point mutations in ras gene result in the production of altered ras P21, lacking GTPase activity. This leads to the occurrence of ras P21 in a permanently activated state, causing uncontrolled multiplication of cells.
Non-receptor tyrosine kinases: These proteins are found on the interior of the inner plasma membrane. They phosphorylate the cellular target proteins (involved in cell division) in response to external growth stimuli. Mutations in the protonogenes (e.g.abl) encoding non-receptor tyrosine kinases increase the kinase activity and, in turn, phosphorylation of target proteins is causing unlimited cell multiplication.
A special category of gene namely cancer suppressor genes or, more commonly, antioncogenes, have been identified. The products of these genes apply breaks and regulate cell proliferation. The loss of these suppressor genes removes the growth control of cells and is believed to be a key factor in the development of several tumors, e.g. retinoblastoma, one type of breast cancer, carcinoma of lung, wilms' kidney tumor.
With the rapid advances in the field of genetic engineering, introducing antioncogenes to a normal chromosome to correct the altered growth rate of cells may soon become a reality.
GENES THAT REGULATE APOPTOSIS
A new category of genes that regulate programmed cell death (apoptosis) have been discovered. These genes are also important in the development of tumors.
The gene, namely bcl-2, causes B-cell lymphoma by preventing programmed cell death. It is believed that over-expression of bcl-2 allows other mutations of protooncogenes that, ultimately, leads to cancer.
UNIFIED HYPOTHESIS OF CARCINOGENESIS
The multifactorial origin of cancer can be suitable explained by oncogenes. The physical and chemical agents, viruses and mutations all lead t the activation of oncogenes causing carcinogenesis. The antioncogenes and the genes regulating apoptosis are intimately involved in development of cancer. A simplification of a unified hypothesis of carcinogenesis is depicted.
The biochemical indicators employed to detect the presence of cancers are collectively referred to as tumor markers. These are the abnormally produced molecules of tumor cells such as surface antigens, cytoplasmic proteins, enzymes and hormones. Tumor markers can be measured in serum (or plasma). In theory, the tumor markers must ideally be useful for screenings the population to detect cancers. In practice, however, this has not been totally true. As such, the tumor markers support the diagnosis of cancers, besides being useful for monitoring the response to therapy and for the detection of recurrence.
A host of tumor markers have been described and the list is ever growing. However, only a few of them have proved to be clinically useful. A couple of the most commonly used tumor markers are discussed hereunder.
1. Carcinoembryonic antigen (CEA): This is a complex glycoprotein, normally produced by the embryonic tissue of liver, gut and pancreas. The presence of CEA in serum is detected in several cancers (colon, pancreas, stomach, and lung). In about 67% of the patients with colorectal cancer, CEA can be identified. Unfortunately, serum CEA is also detected in several other disorders such as alcoholic cirrhosis (70%), emphysema (57%) and diabetic mellitus (38%). Due to this, CEA lacks specificity for cancer detection. However, in established cancer patients (Particularly of colon and breast), the serum level of CEA is a useful indicator to detect the burden of tumor mass, besides monitoring the treatment.
2. Alpha-fetoprotein (AFP): It is chemically a glycoprotein, normally synthesized by yolk sac in early fetal life. Elevation in serum levels of AFP mainly indicates the cancers of liver and germ cells of testis and, to some extent, carcinomas of lung, pancreas and colon. As is the case with CEA, alpha-fetoprotein is not specific for the detection of cancers. Elevated levels of AFP are observed in cirrhosis, hepatitis and pregnancy. However, measurement of serum AFP provides a sensitive index for tumor therapy and detection of recurrence.
CHARACTERISTICS OF GROWING TUMOR CELLS
The morphological and biochemical changes in the growing tumor cells are briefly described here. These observations are mostly based on the in vitro culture studies. Knowledge on the alterations in the biochemical profile of tumor cells guides in the selection of chemotherapy of cancers.
1. General and morphological changes
a) Shape o f cells: Tumor cells are much rounder in shape compared to normal cells.
b) Alteration in cell structures: The cytoskeletal structure of the tumor cells with regard to actin filaments is different.
c) Loss of contact inhibition: The normal cells are characterized by contact inhibition i.e. they form monolayers. Further, they cannot move away from each other. The cancer cells form multilayer's due to loss of cancer free form multilayer's due to loss of contact inhibition. As a result, the cancer cells freely move and get deposited in any part of the body, a property referred to as metastasis.
d) Loss of anchorage dependence: The cancer cells can grow without attachment to the surface. This is in contrast to the normal cells which firmly adhere to the surface. Alteration in the structure of a protein, namely vinculin, is said to be responsible for the loss of anchorage property I cancer cells.
e) Alteration in permeability properties: The tumor cells have altered permeability and transport across the membranes.
2. Biochemical changes
a) Increased replication and transcription: The synthesis of DNA and RNA is increased in cancer cells, indicating an increase in anabolic processes.
b) Increased glycolysis: The fast growing tumor cells are characterized by elevation in aerobic and anaerobic glyolysis. This truly reflects the increased energy demand of multiplying cells.
c) Decreased pyrimidine metabolism: A reduction in the catabolic reactions such as degradation of phyrimiines is observed in tumor cells.
d) Enzyme alteration: The activities of certain enzymes are changed e.g. proteases.
e) Reduced requirement of growth factors:
The tumor cells require much less quantities of growth factors. Despite this fact, there is an increased production of growth factors by these cells.
f) Synthesis of fetal proteins: During fetal life, certain genes are active, leading to the synthesis of specific proteins. These genes are suppressed in adult cells. However, the tumor cells synthesize the fetal proteins e.g. carcinoembryonic antigen, Alfa fetoprotein.
g) Alteration in the structure of molecules:
Changes in the structure of glycoprotein's and glycolipds are observed.
h) Reduced synthesis of certain molecules: A diminished synthesis of specialized proteins is seen in tumor cells.
i) Changes in isoenzymes: The isoenzyme profile of cancer cells is close to the fetal pattern.
j) Alterations in antigens: A loss of regularly occurring antigens coupled with the appearance of new antigens in tumor cells is reported.
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