Cancer is a disorder of the cells which are capable of expressing in all multi cellular organisms (plants & animals). Hunt for the differences between the normal cell and tumour cell begun by the prediction “cancer`s are made of cells” by Johannes Mueller. Mechanism by which the cancer develops is called carcinogenisis it is a multi stage process which involves intiation, promotion and progression. During the intiation primary changes are caused by the carcinogen (agent capable of inducing tumour by acting on the genetic material for by increasing the cell division) its fast and the cells which are initiated by the carcinogen retain for the considerable time. They remain steady until they are initiated by the promoting agents (harmones, normal growth factors) these agents does not cause the cancer by itself but induce the cell division in the initiated tissue. Initiating agents may be various some of them are chemicals, radiations, viruses, genetic structure inside the cell. Before getting deeper in to the subject let us see structures of normal cells and tissues and their growth control mechanisms.
Tissues present in the body can be divided in to four different types.
1. Mesenchyme (supporting tissues): Muscle, blood vessels, cartilage, bone and fibroblasts.
2. Tissue Specific cells: include cells specific to specific organs eg: skin- skin cells, liver-hepatic cells.
3. Reticulo endothelial system: many cells fall in to this system mostly derived from the precursors of the bone marrow. e.g.RBC, WBC, Lymphocytes and Macrophages.
4. Nervous system: its divided in to central and peripheral nervous system.
All the organs present in the body differ in their specific cells, arrangement and distribution of the supporting mesenchyme. All these four different tissues have their own specific cells which maintain the structure and function of their tissues.
Growth control in normal cells: human body has precise growth control mechanism which maintains the organs up to specific size. Better example that can be quoted for the control mechanism is injuries. During the injury of organ/tissue the surviving cells grow and replace the damaged cells as soon as the process finishes the growth terminates /inhabits (i.e growth control mechanism is seen throughout the life of the living beings)
Pictorial representation of cell growth in normal and tumour cell.
Till now we know little about the growth control mechanisms from the past researches we can say there is always a balance between the stimulation and inhabition factors until there is a stimulus for the growth.
Cell division occurs by the growth of the cell components it's similar in all somatic cells. It follows G1- S- G2- M pattern.
it is termed as the resting phase during this phase there is no activity of the cell division. Even though there is some activity seen specific to that cell type (eg: insulin production by the pancreatic cells) the actual cell cycle starts from the G1.
Seems to happen little but we seen some kind of biochemical activity taking place during this phase (eg: protein synthesis which are necessary for the cell division). It`s also known as first check point in the cell cycle which detects the DNA mismatch if it finds any mismatch is stops the cell cycle or sometimes leads to apoptosis. P53 is one of the important regulator protein present during the G1 phase people with low levels of p53 cannot stop the replication of the mismatched DNA this leads to the mutations and cancer.
S-phase/ DNA synthesis phase:
during this phase cells double their DNA content not only DNA several other components increase in their number and then it enters the G2 phase.
it`s the second gap phase were proteins are synthesised more when compared to the G1 and finally the cells enters the Mitotic/M-phase. It`s the second check point during the cell cycle were the un replicated and the mismatched DNA is detected.
it is characterised by the karyokinesis (formation of daughter nucleus) and cytokinesis (formation of daughter cells by the actin and microtubule mediated separation of cytoplasm).As it`s a complex mechanism for our convenience based upon the chromatid position and degree of separation it can be divided in to prophase, metaphase, anaphase, telophase .
Regualtion of the cell cycle:
M-phase promoting factor /MPF was discovered during the extensive research on the two different cell lines. MPF is responsible for the dissolution of the nuclear membrane during the mitosis further research revealed that this MPF works in the presence of cyclins and cyclin-dependent protein kinase. Active MPF is formed by the combination of the cyclin B (levels increase prior to mitosis) and cyclin dependent protein kinases this active form phosphorelates lamin and leads to the dissolution of the nuclear membrane. At the end of the mitotic phase the destruction of the cyclin-B occurs by the poly ubiquitination of the mitotic cyclin which is responsible for the activation of the destruction box present within the cyclin B molecule. As the cyclin B levels decreases the MPF levels also decreases until the cyclin B is increased for the next round of M-phase. Cell cycle is critical and complex process were the check point play an important role in the proper maintenance of the cell cycle. All together there are 3 check points. 1st in G1-phase, 2nd in G2-phase, 3rd in mitotic phase were it arrests the mitotic phase due to improper arrangement of the mitotic spindle.
Any changes in these three checkpoints lead to the mutations and cancer. DNA mutation can be of different types it may be spontaneous, radiation and chemical. Damage in the DNA can be due to depurination, thymine dimerization, deamination e.t.c, there are several enzymes which polymerise and repair the damaged DNA eg: DNA polymerase, AP endonuclease and DNA glycosylases. Any inhibitory defects in these repair enzymes leads to the development of the xeroderma pigmentation (were the individual is more sensitive to UV-light). Combination of all these checkpoints and DNA repair enzyme maintain the cell cycle to occur in the normal way. If there is any changes or alterations there is more chance of transforming the normal cell in to the tumour cell.
It`s bit difficult to determine the tumour cells. We can say that it's the abnormal cell growth which does not respond to the normal growth mechanisms.
Fully developed cancer characterised by the invasion to surrounding tissues/organs and abnormalities in the cell. These tumour cells need the nutrients as if the normal cells which are supplied through the blood. In order to cope up with this tumours produce the tumour angiogenesis factor which stimulates the growth of the blood vessels within the tumours fragments of these tumours circulate across the different parts of the body through blood stream. Tumours developed by this fragment is termed as secondary cancers/tumour metastases).Diagnosis is easier in this case it depends upon the several cellular changes like increase in cell number, irregular arrangement of cells, increase in nuclear size and density, on the surface of the epitheliums eg: cervix of uterus, skin. Coming to the treatments it is difficult when compared to the localised tumours these can be removed surgically or by radiation these tumours lack the capsule as if in the benign tumours and grow in disorganised form.
occurs in most of the tissues but does not invade any other tissues/organs these grow locally and separated from other tissues by a capsule made of the connective tissue. In case of bones and cartilage it produces nodule like structures which are difficult from the normal cells and wart like out growth (contains all cell components) in the tissues of intestinal track, urinary bladder and skin. In some cases only single constituent cell develops in to benign tumour (eg: tumour of the pituitary gland which produces different types of harmones by their respective cells arranged in cords. As the tumour develops (single cell type) makes the cell to produce the excess of the harmone than required. Tumours of the pituitary gland are more than single type which triggers the excess production of more than one type. As we know these tumours does not invade other parts but they cause damage by applying stress to the surrounding normal cells by increasing their size in case of these pituitary tumour it cause excessive pressure over the optic nerves which leads to the blindness. Benign tumours of other harmone producing glands show the similar effects even though it does not invade the surrounding tissues/organs but alter the normal function by producing the excess amounts of the harmones the required.
Proto oncogenes & oncogenes:
Proto oncogene: it encodes the proteins which regulate cell growth and differentiation. It is capable of transforming itself in to oncogene due to it's over expression or by mutation.e.g: genes encoding GTPases involved in signal transduction, extracellular signal regulated kinases involved in the regulation of mitosis and meiosis. Possible reasons for the proto oncogene converting in to oncogene are due to mutations which cause changes in the protein structure and their activities & translocation of chromosomes.
Its a mutated gene capable of converting the normal cell in to tumour cell. Activated oncogene causes the proliferation of the cell instead of the programmed cell death. Activation occurs as follows:
1. Chromosomal rearrangements:
chromosome translocations and inversions it can be seen during the prostate and Ewing tumour.
These mutations enhance the transformation activities in the oncogene. e.g: BRAF gene (with in the kinase domain of this gene mutation occurs at 599 position were valine is replaced to glutamic acid which encodes a protein that stimulates MAP kinase activity which inturn deregulates the genes involved in the cell differentiation, proliferation and survival.
3. Gene amplification:
Better example that cab be quoted for the gene amplification is DHFR(dihydrofolate reductase) gene there are four such genes were we can find more possibility for gene amplification e.g. MYC(its amplification is seen in breast, esophageal, cervical, small-cell lung cancers) Cyclin D1 (seen in hepato cellular, neck & head, breast and esophageal.
Role of this oncogene in carcinogenisis:
From the previous findings it`s found that most of the soft tissue and haemopoietic cancers are due to the activation of oncogene which is accompanied by the alternations in the tumour suppressor genes and also the due to alternations (methylation) in CPG islands present on the promoter sequences of the tumour suppressor genes play important role in the process of carcinogensis. Alterations in mi-RNA also play major role in initiation and progression of the cancers it has both oncogenic and tumour suppressor roles.
mi-RNA belong to the family of non-coding small RNA`s which are 21-25 nucleotide base pairs in length involved in the gene regulation and cellular phenol typing. Recent advances in hepatocellular carcinomas revealed that mir-224 is up regulated. Up regulation of mir-224 causes two important functions which are opposite to each other on one hand it increases the cell proliferation on other hand it leads to sensitisation of cells to apoptosis. Till now oncogenic and tumour suppressive property are two different views of mi-RNA.
Components of the oncogene:
1. Transcriptional factors:
Many of these factors require additional proteins interactions(e.g. JUN transcription factor dimerize with FOS transcription protein and form AP1 transcription factor which is capable of boosting the several gene expressions which regulate the cell division. In case of lymphoid, ewing and prostate cacner even chromosomal translocation can activate the transcription factors(e.g. in case of ewing tumour there is a translocation between chromosome 11 and 22 were the fusion occurs between FLI1 gene of chr-11 and EWS gene of 22 this results in the stimulation of gene transcription. In case of prostate cancer fusion occurs between the TMPR552 gene and the ERG1 or ETV1 gene and leads to the production of fusion protein which boosts the cell proliferation by inhabiting the apoptosis in the prostate glands.
2. Chromatin Remodelers:
ATP-dependent enzymes and enzymes involved in the modification of N-terminal of the histones play important role in the remodelling of the chromatin. This process plays a key role in replication, gene expression, segregation & repair. Interactions between the nucleosomes and chromatin associated proteins are influenced by the epigenetic code which is constituted by the histone modifications.
3. Growth factors:
PDGF (platelet derived growth factor play role in cell proliferation and stimulation of fibroblasts during the process of wound healing. β chain of this PGDF is similar to that of the sis oncogene. over expression of PDGF is observed during the invitro transformation of the fibroblasts with PDGF receptors this leads to the uncontrolled cell division. In case of adenomatous polyposis there occur a changes in APC protein this results in the free β-cantenin which reaches the nucleus through cytoplasm and activates the genes for invasion and proliferation.
Dual Functions of β-Catenin in Cell Adhesion and Transcription.
BCL2 gene plays a key role in follicular lymphomas, lung, lymphocytic leukemia. it inhabits the apoptosis by encoding certain proteins. Proteins homologus to BCL2 homology 3 domain works by inactivating & activating the BCL2, BCL-XL genes and capases(induce apotosis) and also by binding of FAS ligand, Trail and tumour necrosis factor to death receptors present on the cell surface.
Tumour suppressor genes:
These genes encodes a protein which play key role in the inhabition of the tumour growth and it involves in DNA repair and growth control. Any mutations in these genes leads to the development of cancer. Mutations in these genes are recessive in which single allele is sufficient for the inhabition of the tumour growth in order to express phenotypically two alleles must be mutated these mutations are in support of “two-hit” hypothesis proposed by the knudson.
According to this hypothesis tumour suppressor gene is a gene in which one germline mutation leads to the predisposition of cancer in the individual's e.g. 5-10% of the breast cancers are due to inherditary mutations in BRCA1 and BRCA2 gene these two genes are well known as tumour suppressor gene which is involved in transcriptional regulator/DNA repair. This supports the knudson hypothesis were one germline mutation cause the predisposition of cancer and second mutation is acquired during their lifetime. Due to germ line mutation it produces truncated protein which cause loss of function.
Both BRCA proteins maintain the integrity of genome by recombination and DNA repair mechanism even though there is no clear homology between the BRCA1 and BRCA2 there a proposal on how mutation in these genes leads to cancer(due to defective recombinations which inturn alters the integrity of genome and leads of chromosomal rearrangements and mutation). below is the list of tumor suppressor genes, function and their associations in familial cancers.