Disucssion of Tumours abnormalities

Discussion of Tumours abnormalities

molecular basis or biology of cancers include the abnormalities in neoplastic cell behaviour which means the neoplastic cells exhibit different behaviour to normal cells in terms of





Karotype and progression

Stimulate angiogenesis

First tumour cell proliferation

the rate of cell proliferation within any population of cells depends on three things
the rate of tumour cell division: tumour cells can be pushed into the cell cycle more

easily as there is loss of the regulation that controls movement from one phase of the cycle to the next

the fraction of cells within the population undergoing cell division (growth fraction this is the proportion of cells within the tumour cell population that are in the replicative
pool. Not all cells within a tumour are actively replicating and many are quiescent

 the growth fraction is only 20% even in rapidly growing tumours

the rate of cell loss from the replicating pool due to differentiation or apoptosis: overall growth depends on balance between production and loss by apoptosis. in general tumour cells grow faster than they die off

entry G0 cells into the cycle and transition from G1 to S phase are the two crucial regu­lator of the cell cycle. They largely regulate the growth fraction of a cell population

these points are regulated by

 CDK which is regulated
Positively by PDGF,EGFand IGF-1
Negative by TGF-BETA

Neoplastic cells may

• Up regulate their receptors
Mutate intracellular pathways (eg retinoblastoma gene and p53 to evade requirement for these signals

Neoplasms initially grow exponentially and then slow down as they increase is called Gompertzian growth

 Several mechanisms have be explain this change in growth rate with larger tumours

decrease in the growth fraction
Increase in cell loss (eg exfoliation, necrosis
Nutritional depletion of tumour cells resulting from outgrowth of a supply (under adverse conditions tumours may enter G0 until condition improve

latent period :accumulation of cells is slow therefore it can taken several years for a single cell to proliferate into a clinically detectable mass

chemotherapy :chemotheraputics are most effective on cycling cells tumours with a high growth fraction are more susceptible to antinuclear agents debulking tumours or treating with radiation pushes more cells into the cell cycle and therefore increases the number of susceptible cells

 tumour cell differentiation

tumour cells may
Arise at any stage during the process of differentiation and their progeny
can replicated whilst still retaining the characteristics of that

 stage of differentiation

• Tumour cells lose the inverse relationship between proliferation and differentiation
• Tumour cells may de-differentiate
• Tumour cells may change lineage
• Tumour cells may hypomethylate or hypermethylate genes that would control their replication eg p53 is often silenced in this way 3- tumour cell apoptosis

role of apoptosis

 Apoptosis is the process of programmed cell death. It is a controlled sequence of steps that is
activated by a number of signals resulting in suicide of the cell. Most importantly it acts to balance mitotic processes within the body

Apoptosis may be physiological or pathological

. physiological apoptosis
Development: to create organs of normal size and function (eg creation of web spaces between digits
Homeostasis: eg loss of the uterine lining during menstruation or at the tips of the intestinal villi
• immune function: to recognize antigens that are foreign and not of self

pathological apoptosis
Cell damage (eg peeling skin caused by sunburn) and Cell infection
the process of apoptosis
apoptosis occurs as a result of activation of one of two pathways
intrinsic pathway activated from within the cell as a result of DNA damage or other stress
regulated by the bcl-2 family of proteins (pro-apoptotic and anti-apoptotic members) that stabilise the mitochondrial membrane
mitochondria release cytochromes which bind to apoptotic factors and activate cell death via the caspases
Extrinsic pathway activated by apoptotic messages via receptors
via TNF superfamily of proteins and CD95
Common final apoptotic pathway
Activation of a cascade of proteolytic caspase enzymes is the final common pathway to cellular destruction. This manifests as:  Chromatin condensation

 DNA fragmentation

Protein cleavage  Reduction in cellular size and membrane blebbing
Fragmentation of the cell into membrane-enclosed apoptotic bodies
without release of the cell contents into the surrounding environment
Phagocytes engulf and destroy the apoptotic bodies without causing an inflammatory reaction

Loss of the apoptotic pathway is responsible for increased levels of genetic instability accumulation of genetic mutations. This leads to tumour progression by the expansion of clones with more aggressive phenotypes. It also confers resistance to chemotherapy radiation, and immune-mediated cell destruction

The bcl-l gene is particularly important in tumours. The products of this gene represents a

superfamily which associate with each other by homo- and heterodimerisation  some dimers are pro-apoptotic and others are anti-apoptotic. The ratio of anti-apoptotic to pro- apoptotic dimers is important for determining resistance of a cell to apoptosis causing up-regulation of anti-apoptotic dimers or loss of pro-apoptotic dimers overall resistance to apoptosis. Tumours may evade apoptosis by disruption of the control

mechanisms for apoptosis
such as mutation of genes like bcl-2 and BAX

Tumour cell karyotype

The term karyotype refers to the chromosomal arrangement of the genetic material in the cell. Virtually all solid tumours, including the non-Hodgkin's lymphomas, have mal karyotype or chromosomal abnormalitv. Some of these abnormalities are limited to

given tumour type almost like a genetic fingerprint . A good example of Philadelphia chromosome characteristic of chronic myelocytic leukaemia CMl

Types of chromosome abnormality

 Gain/loss of whole chromosome aneuploidy
 Partial deletion
 Translation from one chromosome to another
 Inversion of a segment of chromosome
Re-arranging genetic material in this fashion has implications for the control of expression of the genes in the abnormal segment. It may place oncogenes in a highly transciptionally active region of the genome or lead to deletion of tumour suppressor genes


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