Download Neoplasia Etiology genetic Neoplasia is defined as: "an abnormal

Neoplasia
Etiology genetic
Neoplasia is defined as: "an abnormal mass of tissue, the growth of which exceeds
and is uncoordinated with that of the normal tissues and persists in the same excessive
manner after cessation of the stimuli that evoked the change."
Neoplasia has genetic and environmental causes. It is important to note that both
play parts in causing neoplasia.
Genetic evidence of tumourigenesis
Introduction of genes (activated oncogenes) in normal cells in culture make them
transformed.
Patients with familial cancers have siblings with relatively higher risk of developing
cancer. For example, mutation of BRCA-1 and BRCA-2 (Breast cancer) genes are
linked to Familial breast and ovarian cancer.
Patients with well-known inherited cancer syndromes in which inheritance of a single
mutated gene have increased Risk of developing tumours.
Etiology environmental
The environment we live in is filled with cancer causing agents (Table 1).
This can either be explained by differences in the Genetic make-up of different races
or more likely that the environment different people live in has different carcinogens.
We know that Death from skin cancer (Melanoma) are 6 times more frequent in
Australia and New Zealand (white settlers exposed to the sun) than in Iceland, which
is probably attributed to exposure to the sun. Also, The death rates from stomach
cancer in both men and women In Japan is seven to eight times more common than in
Europe or the U.S.A. Why is that? Well It could be that the Japanese have some small
different genetic make up that makes them more Susceptible to stomach cancer than
the Americans but it is more likely that the Japanese are Exposed to some carcinogens
that the Americans are not.
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Table 1: Carcinogenic agents and occupational cancer
Agent
Occupation
Cancer Site
Ionizing radiations
radon
certain underground miners
bronchus
X-rays, radium
radiologists, radiographers
skin
Radium
luminous dial painters
bone
Ultraviolet radiation
farmers, sailors, etc.
skin
Polycyclic hydrocarbons
in soot
chimney sweepers,oil workers
scrotum, skin, bronchus
2-Naphthylamine; 1naph-thylamine
rubber workers
bladder
Benzidine; 4aminobiphenyl
chemical workers
bladder
shipyard and insulation
workers
Mesothelioma lung
sheep dip manufacturers, gold
miners
skin and bronchus
Benzene
workers with glues, varnishes,
etc.
marrow (leukemia
Vinyl chloride
PVC manufacturers
liver (angio-sarcoma)
Aflatoxin B1
Food storage. Due to growth of
Aspergillus flavus (fungi)
Liver
Benzo(a)pyrene
Smokers
Lung
Asbestos
Arsenic
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Molecular basis of neoplasia
Cancer arises from nonlethal genetic damage which can be transmitted to cell
progeny. Most tumors initially develop as monoclonal, arising from a single mutated
cell.
Three kinds of genes are targets for carcinogenic transformation:
1) proto-oncogenes promote cell growth and require the alteration of only one allele
?to create out of control cellular growth (dominant gene)
2) tumor suppressor genes inhibit cell growth and require the alteration of both
alleles to affect cell growth (recessive oncogenes), DNA repair genes are similar
3) genes that regulate apoptosis may be dominant or recessive but influence the
ability of the cell to target itself for destruction following cell damage
Neoplasia : Molecular basis of neoplasia : Oncogenes
Proto-oncogenes are normal cellular genes that regulate cell growth, division, and
differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes by
mutation, retroviral transduction, gene amplification, or dislocations.
Classes of Oncogenes:
Growth Factors: Genes that encode growth factors may become oncogenic.
Growth Factor Receptors: most are transmembrane proteins that cause
phosphorylation of proteins on the cytoplasmic side when activated. Point mutations
in the ret protooncogene (codes for receptor associated with glial cells) are associated
with MEN and familial medullary thyroid carcinoma. Growth factor receptors may
also be overexpressed.
Signal Transducing Proteins: these proteins exist on the inner plasma membrane
and following activation work to phosphorylate cytoplasmic proteins. Translocation
of the signal transducing protein (non-receptor associated) c-abl on chromosome 9 to
the bcr region of chromosome 22 activates it to increase cell growth.
Nuclear Transcription Proteins: these proteins influence DNA synthesis in the
nucleus.
Cyclins and CDKs: CDKs are present within the cell at all times and help the cell
through the cell cycle. CDK4 mutation seems to be implicated in melanomas and
other cancers.
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Methods of Activation of Oncogenes:
1. Point mutations: typical of ras proteins
2. Chromosomal rearrangements: translocation may associate a growth factor or
receptor with an actively transcribed area, or result in the formation of an active
hybrid protein.
3. Gene Amplification: duplication, multiplication of DNA sequences in the genome.
Associated with N-myc In neuroblastoma and c-erb 2 in breast cancer.
Carcinogens/process of carcinogenesis
Carcinogens are agents that have the ability to initiate the formation of cancer. They
are divided into 4 groups:
1. Chemical Carcinogens
2. Physical Agents
3. Ionizing Radiation
4. Oncogenic Viruses
It is useful to remember that 80 - 90% of all cancers may be related to environmental
agents including diets, lifestyles, and viruses. Several environmental agents often act
together (co-carcinogenesis).
Ultraviolet Light
Strong epidemiologic relationship to squamous cell, basal cell, and melano-carcinoma
in fair skinned people.
Ionizing Radiation
Ionizing radiation includes: X-rays, gamma rays, as well as particulate radiation;
alpha, beta, positrons, protons, neutrons and primary cosmic radiation. All
forms are carcinogenic with special sensitivity in:
Thyroid: Carcinoma occurs in 9 % of those exposed during infancy or childhood.
Lung: Increased frequency of lung cancer in miners exposed to Radon gas.
Viral Carcinogenesis
A large number of RNA and DNA viruses have been implicated in the causation of a
variety of cancers in animals and humans some important ones are listed below.
Human papiloma virus (HPV).
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Epstein-Barr Virus (EBV) is a member of the Herpes family. It is associated with 4
types of human cancers:
1. African Burkitt lymphoma
2. B-cell Lymphoma (particularly in immunosuppressed individuals)
3. Hodgkin lymphoma
4. Nasopharyngeal carcinoma
Hepatitis B virus is associated with increased risk of developing hepatocellular
carcinoma
RNA viruses like Human T-Cell Leukemia Virus Type 1 (HTLV) is associated
with some forms of T-Cell leukemia/Lymphoma.
Cancer metastasis
Adhesion to endothelial cells
Tumour cells express E-Selectins
Molecules that bind to
Sialyl-Lewis X on endothelial cells
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