In the normal circumstances , the proliferation of body cells is under strict control. The cells differentiate , divide and die in a sequential manner in a healthy organism . Cancer is characterized by loss of control of cellular growth and development leading to excessive proliferation and spread of cells. Cancer is derived from a Latin word meaning crab. It is presumed that the world cancer originated from the character of cancerous cells which can migrate and adhere and cause pain (like a crab) to any part of the body.
Neoplasia literally means new growth. Uncontrolled growth of cells results in tumors (a word originally used to represent swelling). Oncology (Greek : oncos – tumor) deals with study of tumors.
The tumors are of two types.
1. Benign tumors : They usually grow by expansion and remain encapsulated in a layer of connective tissue. Normally benign tumors are not life-threatening e.g. moles ,warts. Theses types of benign tumors are not considered as cancers.
2. Malignant tumors or cancers : They are characterized by uncontrolled proliferation and spread of cells to various parts of the body, a process referred to as is metastasis . Malignant tumors are invariably life-threatening e.g. lung cancer , leukemia.
About 100 different types of human cancers have been recognized . Cancers arising from epithelial cells are referred to as carcinomas while that from connective tissues are known as sarcomas. Methods for the early detection and treatment of cancers have been developed . However little is known about the biochemical.
Incidence
Cancer is second largest killer disease (the first being coronaty heat disease) in the developed countries. It is estimated that cancer accounts for more than 20% of the deaths in United States. Based on the current rate o incidence it is believed that one in every 3 person will develo0p cancer at come time during his life.
Although humans of all age develop cancer, the incidence increases with advancement of age. More than 70% of the new cancer cases occur in persons over 60 years. Surprisingly, cancer is a leading cause of death in children in the age group 3- 13years m half of them die due to leukemia.
ETIOLOGY
In general, cancer are multifactorial in origin. The causative agents include physical, chemical ,genetic and environmental factors. A survey in USA has shown that about 90% of all cancer deaths are due to avoidable factors such as tobacco, pollution, occupations, alcohol and diet.
Most of the cancers are caused by chemical carcinogens radiation energy and viruses. Theses agents may damage DNA or interfere with its replications or repair.
Chemical carcinogens
It is estimate that almost 80% of the human cancers are caused by chemical carcinogens in nature .The chemical may be organic (e.g. dimethylbenzanthracene, benzo (a) pyrene, dimethyl nitrosamine) or inorganic (arsenic, cadmium ) in nature. Entry of the chemicals into the body may occur by one of the following mechanisms.
1. Ocupation e.g. asbestos, benzene.
2. Diet e.g aflatoxin B produced by fungus (Aspergillus flavus) contamination of foodstuffs , particularly peanuts.
3. Drugs – certain therapeutic drugs can be carcinogenic e.g. diethylstibesterol.
4. Life style e.g. cigarette smoking.
Mechanism of action : Although a few of the chemicals are direct carcinogenic , majority of them require prior metabolism to become carcinogenic . The enzymes such as cytochrome P450 responsible for the metabolism of xenobiotics (Chapter 24) are involved in dealing with the chemical carcinogens. In genera, a chemically non reactive procorcinogen is converted to an ultimate carcinogen by a series of reactions.
The carcinogens can covalently bind to purines , pyrimidines and phosphodiester bonds of DNA , often causing unrepairing damage . The chemical carcinogens frequently cause mutations (a change in the nucleotide sequence of (DNA) which may finally lead to the development of cancer, hence they are regarded as mutagens.
Ames assay : This is a laboratory test to check the carcinogencity of chemicals. Ames assay employs the use of a special mutant strain of bacterium , namely salmonella typhimurium (His-). This organism cannot synthysize histidine ; hence the same should be supplied in the medium for its growth. Addition of chemical carginogens causes mutations (reverse mutation) restoring the ability of the bacteria to synthesize histidine (His+) in the colonies of agar plates , the chemical mutagens can be identified. The Ames assay can detect about 90% of the chmical carcinogens. This test is regarded as a preliminary screening procedure. Animal experiments are conducted for the final assessment of carcinogencity.
Promoters of carcinogenesis : Some of the chemicals on their own are not carginogenic . Certain substances known as promoting agensts make them carcinogenic. The application of benzo(a) pyriene to the skin, as such , does not cause tumor development, however , if this is followed by the application of croton oil, tumers will develop. In this case , benzo(a)pyrene is the initiating agents while croton oil acts as a promoting agent or promoter. Several compounds that act as promoting agents in various organs of the body have been identified. These include saccharin and Phenobarbital.
Radiation energy
Ultraviolet rays, X-rays and y-rays have been proved to be mutagenic in nature causing cancers. These rays damage DNA which is the basic mechanism to explain the carcinogenicity of radiation energy. Fro instance, exposure to UV rays results in the formation of pyrimidine dimmers in DNA while X-rays cause the production of free radicals. This type of molecular damages are responsible for the carcinogenic effects radiations.
Carginogenic viruses
The involvement of viruses in the etiology of cancer was first reported by Rouse in 1911. He demonstrated that the cell-free filtrated from certain chicken sarcomas (tumors of connective tissues) promote new sarcomas in chicken. Unfortunately , this epoch-making discovery of Rouse was ignored for several years. This is evident from the fact that Rous was awarded the Nobel Prize in 1966 at the age of 85 for his discovery in 1911!
Selected Tumor viruses
Class Members
DNA viruses
Adenovirus Adenovirus 12 and 18
Herpesvirus Epstein-Barr virus, herpes
Simplex virus
Papovirus Papilloma virus, polyoma virus
 |
RNA viruses
Retrovirus type B Mammary tumor virus of mouse
Retrovirus type C Leukemia, sarcoma
The presence of viral particles and the enzume reverse transcriptase , besides the occurrence of base sequence in the DNA of malignant cells, complementary to tumor viruses indicate the involvement o fviruses in cancer, The viruses involved in the development of cancer, commonly known as oncognic viruses, may contain either DNA or RNA. A selected list of tumor viruses is given in table.
DNA the ultimate in carcinogenesis
DNA is the ultimate critical macromolecule in carcinogenesis.. This fact is supported by several evidence
1. Cancer are transmitted from mother to daughter cells. In other words , cancer cells beget cancer cells.
2. Chromosomal abnormalities are observed in many tumor cells.
3. Damage to DNA caused by mutations often results in carcinogenesis.
4. Laboratory experiments have proved that purified oncogenes can transform normal cells into cancer cells.
MOLECULAR BASIS OF CANCER
Cancer is caused by a genetic change in a single cell resulting in its uncontrolled multiplication . Thus tumors are monoclonal. Two types of regulatory genes – oncogenes and antionconges 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.
Oncogenes
The genes capable of causing cancer known as oncongnes (Greek : oncos-tumor or mass). Oncogenes were originally discovered in tumor causing viruses. These viral oncogenes were found to be closely similat to certain genes present in the normal host cells which are referred to as protooncogenes . Now about 40 viral and cellular protooncogenes have been identified, 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, soe of the ipotant onesare described hereunder.
1. Viral insertion into chromosomes : When certain retroviruses (genetic material RNA) infect cells , a complementary DNA (c DNA) is made from their RNA by the enzyme reverse trascriptase. The c DNA so produced gets inserted into the host genome(fig. 30.1). The integrated double-stranded c DNA is referred to as provirus, This pro-viral DNA takes over the control of the trascrption of cellular chromosomesDNA and transforms the cells. Activation of protooncogenes myc to oncogene by viral insertion ultimately causing carcinogenesis is well known (e.g.avian leukemia).
Selected oncoproteins, protooncongenes and associated cancers
Oncoproteins Protooncogene Associated human cancer(s)
Growth factors
Platelet derived growth facto sis Osteosarcoma
Epidermal growth factor (EGF hst-1 Cancer of stomach, breast and
Bladder
Growth factor receptors
erb-B1 Lung cancer
erb-B2 Stomach cancer
erb-B3 Breast cancer
Signal – transducing proteins
GTP – binding proteins ras Leukemias, cancers of lung,
Pancreas and colon
Non receptor tyrosine kinase abl Leukemia
Some DNA viruses also get inserted into the host chromosomes and activate the protoonocongenes.
2. Chromosomal translocation : Some of the tumers exhibit chromocomal 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 overexpression 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 leading to the increased synthesis of certain proteins which make the cell malignant.
3. Gene amplification : Severalfold amplifications of certain DNA sequence are observed in some cancers. Administration of anticancer drugs methotrexate (an inhibitor of the enzyme dihydrofolate reductase is associated with gene amplification. The drug becomes inactive due to gene amplification resulting in a severalfold (about 400) increase in the activity of dihydrofolate reductase
4. Point mutation : The ras protoonocogene is the best example of activation by point mutation (change in a single base in the DNA) . The mutated ras oncogene produces a protein (GT Pase) 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 of ras mutation is detected in several human tumors – 90% of pancreatic ,50% of colon and 30% of lung. However, ras mutations have not been detected in the breast cancer.
Selected polypeptide growth factors
|
Growth factor Soure(s) Major function(s)
 |
Epidermal growth factor(EGF) Salivary gland, fibroblasts Stimulates growth of epidermal
And epithelial cells
Platelet derived growth factor Platelets Stimulates growth of mesenchy-
mal cells,promotes wound healing
Transforming growth factor Epithelial cell Similar to EGF
Transforming growth factor Platelets, kidney,placenta Inhibitory(sometimes stimulatory) effect
On cultured tumor cells
Erythropoietin Kidney Stimulates development erythropoetic
Cells
Nerve growth factor (NGF) Salivary Stimulates the growth of sensory and
Sympathetic neurons
Isulin like growth factors Serum Stimulates incorporation of sulfates
(IGF-l and IGF-llrespectively cartilage; exerts insulinike action on
Known as somatomedins C and A certain cells
Tumor necosis factor (TNF-a) Monosytes Necosis of tumor cells
Interleukin -1 (IL-1) Monosytes, Leukosyts Stimulates synthesis of IL-2
Interleukin-2 (IL-2) Lymphosyts Stimulates growth and maturation of
(mainlyT-helper cells). T-cells
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 cellos . Some of the products of oncongenes are discussed below.
Growth factor : Several growth factors stimulating the proliferation of normal cells are known. They regulate cell division by transmitting the massge across the pasma memdbrane to the interior of the cell (transmembrrane signal transduction). It is believed that growth factors play a kwy roe in carcinogenesis.
A selected list of polyuproptide growth factors, their xources and majoe functions are given in Table 30.3
The proliferation is stimulated by growth factors. In general, a growth factor binds to a protein receptor on the plasma membrane. This binding activates sytoplasmic protein kinases leadingto the phosphorylation of intacellular trget proteins. The phosphorylated proteins, in turn, act as intracellular messengers to stimulate cell division , the mechanism of which is not clearly known.
Transforming growth actor (TGF –a ) is a protein synthesized and required for the growth of epithelial cells. TGF-a is produced in high concerntration in individuals suffering from psoriasis, a disease characterized by excesibe proliferation of epidermal cells.
Growth factor receptors : Some oncongens encoding growth actor receptors have been identified . Overexpression and /or structural alterations in growth factor receptors are associated wth eacinogensis. For instance the overexpression of gene erb-B encoding EGF-receptor is observed in lung cancer.
GTP-binding protein : These are a group of signal transducing proteins. Guanosine triphospate (GTP) – binding proteins are found in about 30% of human cancers. The mutation of ras protooncogene is the single most dominant cause of many human tumors.
The involvement of ras gene) with a moleculat weight 21,000 (P21) in cell multiplication is illustrated in fig. 30.3 . The inactrve ras is in a bound state with GDP. When the cells are stimulated by growth factors ,ras P21gets activated by exchanging GDP for GTP. This exchange process is catalysed by guanine mucleotide releasing factor (GRF). The active rasP21 stimulatesreglators such as cyutoplasmickinases, ultimately causing DNA replication and cell division. In normal cells the activity of ras P21 is shortlived. The GT Pase activity, which is and integral part (intrinsic) of ras P 21 gydrolyses GTP to GDP, reverting ras 21 to the original state. There are certain proteins namely GTPase activating proteins (GAP) , which accelerate the hydrolysis proteins (GAP), which accelerate the hydrolysis of GTP of ras P21 . Thus in normal cells , the activity of ras P21 is 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 interioe of the inner plasma embrane. They phophorylate the cellulat target proteins (involved in cell division) in response ot external growth stimuli. Mutations in the protooncogenes (e.g. abl) encoding non receptor tyrosine kinases increase the kinase activity and ,in turn , phosphorylation of target proteins causing unlimited cell multiplication.
Antioncogenes
A special categoty of genes namely cancersuppressor genes or more commonly antioncogenes have been identified . 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 tumer.
With the rapid advances in the field of genetic engineering, introducing antioncogenes to a normal chromosomes to correct the altered growth rate of cells may soon become a relity.
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 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 vruses and mutations all lead to the activation of oncogenes causing carcinogenesis. The antioncogenes and the genes regulating apoptosis are intimately involved in development o f cancer . A simplification of a unifield hypothesis of carcinogenesis is depicted in 30.4
Selected tumor markers and associated cancers
Tumor marker Associated cancer(s)
Oncofetal antigens
Carcinoembryonic antigen (CEA) Cancers of colon, stomach, lung pancreas and breast
Alpha fetoprotein (AFP) Cancer of liver and germ cells of testis
Cancer antigen – 125 (CA-125 Ovarian cancer
Harmones
Human chorionic gonadotropin (hCG) Choriocarcinoma
Calcitonin Carcinoma of medullary thyroid
Catecholamines and thrit Pheochromocytoma and
Metabolites (mainly vanillyl mandelic acid neuroblatoma
Enzymes
Protatic acid phosphatase Prostate cancer
Neuron specific enolase Neuroblastoma
Specific proteins
Prostate specific antigen (PSA) Prostate cancer
Immunoglobulins Multiple myeloma
Tumor markers
The biochemical indication employed to detect the presence of cancers are collective referred to as tumor markers . These are the abnormally produced molecules of tumor cells such as surface antigens, cytoplasmic proteins, enzymes and hormones. Tumer markers can be measured in serum (or plasma). In theory, the tumer markers must ideally be useful for screening the population to detect cancers. In practive, however, this has not been totally true. As such, the tumer markers support the diagnosis of cancers, besides being useful for monitoring the response to therapy and for the early detection of recurrence.
A host of tumer markers have been described and the list is evergrowing. However only a few of them have proved to be clinically useful. A selected list of tumor markers and the associated cancers are given in table 30.4
Acouple of the most commonly used tumor markers are discussed hereunder.
1. Carcinoembryonic antigen (CEA) : This is a complex glycoprotein, produced by the embryonic tissue of liver , gut and pancreas. The presence of CEA in serum is detected in several cancers (colon, pancreas, stomach, 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 diabetes mellitus (38%). Due to this CEA lacks specificity for cancer detection. However in established cancer patients (particularly of colon and breasts) the serum level of CEA is a useful indicator to detect the burden of tumor mass, besides monitoring the treatment.
2. Alpha-fetopritein (AFP) : It is chemically a glycoprotein, normally synthesized by yolk sac in early fetal life. Elevation in serum level and germ cells of stesits 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 observation are mostly based on the in vitro culture studies . Knowledge on the alterations in the selection of chemotherapy of cancers.
1. General and morphological changes
· Shape of cells : The tumor cells are much rounder in shape compared to normal cells.
· Alterations in cell structures : The cytokeletal structure of the tumor cells with regard to actin filaments is different.
· Loss of contact inhibition : The normal cells are characterized by contant inhibition i.e. they form monolayers . Further they cannot move awayfrom each other. The cancer cells form multilayers due ot loss of cntact inhibition (Fig. 30.5) . As a result the cancer cells freely move and getdeposited in anyu part of the body , a property referred to as metastesis.
· Loss of anchorage dependence : The cancer cells can grow without attachment to the surface . This is in cantrast 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 in cancer cells.
· Alteration in permeability properties : The tumor cells have altered permeability and transport across the membranes.
2. Biochemical changes
· Increased replication andtranscription : The synthesis of DNA and RNA is increased in cancer cells, indicating an increase in anabolic process.
· Increased glycolysis : The fast growing tumors cells are characterized by elevation in aerobic and anaerobic glycolysis . This truly reflects the increased energy demands of multiplying cells.
· Decreased pyrimidine metabolism : A reduction in the catabolic reactons such as deradation of pyrimidines is observed in tumor cells.
· Enzyme alterations : The activities of certain enzymes are changed e.g. proteases.
· Reduced requirement of growth factors : The tumor cells required much less wunatities of growth factors. Despite this fact, there is an increased production of growth factors by these cells.
· 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 tumors cells sythesizze the fetal proteins e.g. carcinoembryonic antigen, alfa fetoprotein.
· Alterations in the structure of molecules : Changes in the structure of glycoproteins and glycolipids are observed.
· Reduced sythesis of certain molecules : A diminished synthesis of specialized proteins is seen in tumor cells.
· Changes in isoenzymes : The isoenzyme profile of cancer cells is close to the fetal pattern.
· Alterationin antigens : A loss of regularly occurring antigens coupled with the appearance of new antigens in tumor cells is reported.
Metastesis
Metastesis refers to the spread of cancer cells from the primary sits of origin to other tissues of the body where they get deposited and grow as secondary tumors .Metastasis is the major cause of cancer related morbidity and mortality. The biochemical basis of metastasis is not clearly known. It is believed that the morphological changes in tumor cells , loss of contact inhibitions in the structure of certain macromolecules are among the important factors responsible for metastasis.
BIOMEDICAL/ CLINICAL CONCEPTS
· The incidence of cancer increases as age advances, more than70% of the new cases occurring in persons over 60.
· About 80% of the humanconcers are caused by chemical carcinogens.
· The products of oncognes (growth factors, GTP- binding proteins) have been implicated in the development of cancer. Antioncogenes apply breaks and regulate the cell proliferation.
· The physical and chemical agents , viruses and mutations result in the activation of oncogenes causing carcinogenesis.
· The abnormal products of tumor cells, referred to as tumor markers (CEP,AFP,PSA) are useful for diagnosis and prognosis of cancer.
· Knowledge on the alterations in the biochemical profile of tumor cells is helpful for the chemotherapy of cancers.
SUMMARY
1. Cancer is characterized by uncontrolled cellulat growth and development , leading to excessive proligeraion and spread of cells. Cancer is the second largest killer disease (next to heart disease ) in the developed world.
2. Regulatory genes – namely oncogenes, antioncogenes and genes controlling cell death- are involved in the development of cancer. Activation of oncognes is a fundamental step in carcinogenesis. This may occur by insertion of viral DNA into hostr chromosome, translocation of chromosomes, gene amplification and point mutation.
3. The product of activated oncogenes such as growth factors growth factor receptors, GTP-binding proteins, nonreceptor tyrosine kinases have all been implicated in the development of cancer.
4. Tumor markers of cancers include conrcinoembryonic antigen (CEA) alpha froprotein (AFP) cancer antigen – 125 and prostate specific antigen (PSA). They are mainly useful to support diagnosis, monitor therapy and detect recurrence.
5. There are several morphological and biochemical change in the tumor cells which distringuish them from the normal cells . The cancer cells are characterized by loss of contact inhibition altered membrane transport increased DNA and RNA synthesis increased glycolysis alteration in the structure of certain molecules etc.
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