Normal cell division regulation and the development of cancer

Cancer Cell Biology

The fundamental unit of life is the cell and in the body it is the smallest structure exhibiting performance capability of all the processes defining life. Specialized cells are contained in each of the body organs like the lungs, colon, breast and brain which are able to perform the particular function in the body such as digestion, oxygen transportation, locomotion and excretion. Proper performance of the organs is ensured through its replacements when they get worn out which are injured and in particular responding to the changes in the environment. For instance the production of oxygen is increased by the bone marrow in response to high altitude or bleeding. Also during an infection there is rapid production of certain white blood cells. Cell reproduction is through a cell division process and this is highly regulated in the normal cells. DNA is the responsible for the cell inheritance, growth and containment. The DNA which acts as the brain of the cell is highly intricate molecule that the cell nucleus manufactures. The blue print of everything done by the cell is the DNA. The chromosomes are the distinct arrangements of the DNA in the human cell and they are 46 of them. There is pair arrangement of the chromosomes characterized by each biological parent giving 23 chromosomes (Pelengaris et al., 2006, p.25).

Specific location on a chromosome is occupied by each gene. Different proteins are made through the instruction of the each gene through various biochemical steps. Structural proteins are manufactured by some genes instructions which act as the building blocks. The cell is instructed to produce growth factors, hormones and cytokines by other genes which communicate with other cells after exiting the original cell. Regulatory proteins are produced by other genes and these are responsible for other protein functions control or instructs other genes when to turn "off" or "on." RNA is manufactured when the gene gets turned on and this is a complex molecule containing the information required for new protein formation.

When the proper signal is received by the cell, it then under goes division and this signals circulate the bloodstream originating from growth factors. The cell undergoes a cell cycle when the messages for dividing are received by the cell and this involves several division phases. The proper execution of these events is monitored by the checkpoints in each step. For proper cell division, all these processes should take place because the cell reproduction involves many processes. A cell develops to be cancerous if something goes wrong in the process. An uncontrolled cell is cancerous because they don't pay attention to signals instructing the end of the division process, shed or die unlike the normal cells (Seer Training Module, 2002).

Understanding cancer from cell biology / Cellular understanding of cancer

A lot of information can be obtained from the studying of the cancer cells characteristics though inferences made from the whole organism appearance and laboratory observations. A unified view of the cancer disease has been constructed by the scientists from the various key understandings resulting from the cellular biology study of the cancer. For instance a major understanding from this is that the cancers cells are actually indigenous cells which then become abnormal and they come from the normal body tissues. Moreover almost all the tumors which are malignant are monoclonal in their origin and this means they came from one ancestral cell which was transformed somehow to a cancerous state from the normal state. Even though these insights seem straightforward, they were not easily reached. A question that was raised is the manner in which a cell pedigree of cell mass which would be known as a tumor eventually be described.

The transplanting of the tissues from persons to persons was one of the approaches attempting to identify the cells which were cancerous. As the involved people became more distantly related, the less the transplants seem to work but they worked well in the twins who were identical. The distinction by the immune system of the recipient between the foreign origin cells and the cells which have lived in the self always is the barrier to the successful transplantations. The classification of the tissues as either non-matching or matching before the organ or tissue is grafted in to the body of another person is one of the practical application of this discovery. The tumor cells of a specific patient of cancer have been shown to be cell types as those of tissues which are normal and located in the other parts of the person's body as has been revealed by these tests of tissue typing when conducted on the cancer cells. Therefore tumor arises from the tissue of the person and not through infections which can introduce the cells from the body of another person (Pelengaris et al., 2006, p.307).

From two scenarios which are distinct which will aid in explaining the development of the cancer cells within the normal tissue, we can know the monoclonal nature of the tumors. The first being because the tumor which results from the many cells becoming cancerous is a representation of the original cell descendants. Therefore the tumor nature is considered polyclonal. The second scenario is that the resulting tumor is a representation of the cell descendants which in this case it's the only one that is transformed to a cancerous from a normal cell.

There has been difficulty in the obtaining the direct for almost all malignant tumors evidence which will support the monoclonal origin due to the absence of obvious distinguishing marks in the tumor cells and these are used in their clonal relationship demonstration. Indication of this relationship can however be done by using one cellular marker for the relationship indication by the scientist: the X-chromosome is inactivated and its occurrence is in about all the human female body cells. During the embryonic development of the females, the inactivation of the X-chromosomes occurs randomly. Having disparate X-copies turned off or on in the disparate body cells makes the female like a mosaic. The same inactivation of chromosomes is present in the future cell generations originating from the cell which was inactivated initially and this is either the paternal or maternal X. It can therefore be inferred that tumor cells originated form one ancestral cell by observing that there is the same X chromosome inactivation in the cells within the tumor.

Therefore cancer is a disease which one body cell which is normal goes through a genetic transformation to become the cancer cell. The population of cells produced from the proliferation of this cell and its descendants over several years which is thus referred to as tumor. The symptoms experienced by the individual as cancer are produced by the tumor. Tumor formation is not completely described in its involved events by this account even though it is accurate. The cells constituting the tumor become differ from each other with time due to the novel traits which have been acquired as the tumor develops as has been revealed by additional research. Distinct cell subpopulations are formed within the tumor. Therefore the cells which have experience these changes are able to compete against cells which don't have the complete changes set. Thus a series of clonal expansions leads to the cancer development which is from one ancestral cell. The biology of cancer cells led to another critical understanding that there are a lot of differences shown by these cells from the normal cells. For instance, cancer cells are not stable genetically and prone to duplications, rearrangements and chromosomes deletion which results to their progeny having usual trait. Hence the tumor can have many cells with different characteristics even though its origin is monoclonal.

There are differences in the way in which the cancer cells look and act when compared to the normal cells. The nucleus of the cancerous cell can be so large that most of the volume of the cell is occupied by it while the normal cell the nucleus is only one-fifth the cell's size. The normal cell's differentiated traits are usually not present in the tumor cells of which they are the descendants of those cells. Whereas mucus is produced and released by the normal secretory cells, these characteristics may be lost in the cancer cells. Similarly large quantities of keratin is contained in the epithelial cells, this protein may not be accumulated in the cytoplasm of the skin cancer cells (Weinberg, 2006, p.29).

However the growth restraint characterizing the normal cells is lost in the cancer cells and this is the principal difference between the cancerous cells and the normal cells. Significantly mitosis is engaged by a large number of the tumor cells whereas the normal tissues rarely have the mitosis process. Several unusual characteristics are demonstrated by the cancer cells when they are grown in culture and these are the contact inhibition absence and reduced reliance on the growth factors present in the environment. There is no cooperation of the cancer cells with other cells present in the environment and this is contrast to the normal cells. In the tissue culture, they usually proliferate indefinitely. The normal constraints which limit the growth of the cells absent in the cancerous state and are also characterized by the division ability for number of generations which is unlimited.

Cell cycle and cancer

With millions of chemical reactions taking place concurrently and in specific areas, the human body can be thought of as a small laboratory. It is the only "machine" with the ability to save fuel when fed in excess and also know to bring out the reserves when facing starvation, capable to protect itself from attacks by viruses and bacteria, ability to make adjustments to withstand changes of weather and the ability to learn, think and create on its own. The human body system is well integrated and organized, able to perform vital functions important to its survival. Malfunctions in the body can have damaging results that range in severity from discomfort to life threatening illnesses. Many processes and reactions taking place within the cells are tightly controlled, an example being cell division. Cell division involves a series of reactions and changes like DNA replication and protein synthesis involving cooperation between arrays of proteins to achieve a common goal.

Cell division is divided into four phases where normal cell division progresses from one phase to the next with strictly controlled "checkpoints." These serve as safety measures for the cell that prevent the control system from dictating the start of another cell cycle event before the previous one as finished or before any damage to the cell has been repaired accordingly. The cell division cycle also depends on external cues. In case cell division is unregulated, and is independent of the external cues, there is possibility of one developing cancer, one of the most devastating diseases in the world (Michor & Nowak, 2004, p.203).

Cell division cycle starts with the growth phase, followed by synthesis, second growth and mitotic phases. On receiving external cues, from growth factors released from neighboring cells, so as to initiate division, the cells move into the growth phase. Here, cells prepare for division by producing more proteins. DNA replication by the cells takes place in the synthesis phase. This brings about creation of identical copies to enable daughter cells inherit an exact copy of the DNA. In the second growth phase, synthesis of the proteins needed for the growth of the daughter cells takes place. The cell separates its DNA and divides into two in the mitotic phase.

Cell division requires the accurate replication and segregation of chromosomes. All the tasks are accomplished in an orderly manner if all the events related to cell division are coordinated throughout the cycle. An example is where cell division occurs before it attains its optimum size and as a result, smaller daughter cells result from the subsequent division. A set of interacting proteins forms the cell control system which is responsible for regulating the process of cell division. This system of proteins directs and coordinates other proteins that are involved in particular tasks like DNA replication. The control system still has to follow feedback signals from the cell cycle itself in spite of its ability to act on other proteins. There are other proteins in the cell cycle involved in surveillance control mechanisms. They are able to stop or delay the control systems' progress at the cycle checkpoints. The loss or inactivation of a gene encoding a protein in the surveillance system can result in susceptibility of developing cancer.

The cell cycle's control system is based on two families of proteins: namely the cyclins and cyclin-dependent kinases (CDK). The CDKs phosphorylate (add a phosphate group) key amino acid residues thus induce other proteins to perform their functions. Cyclins control the CDKs ability to phosphorylate by binding to the CDKs.

Many proteins involved in the surveillance system can delay or terminate the cell cycle progress. Some promote rapid degradation of cyclins and others prevent entry of CDK-cyclin complexes into the cell compartments where they are needed for cell cycle progression. The first checkpoint a cell encounters before entering a cycle is at transition between the dormant and growth phases. Retinoblastoma (Rb) gene is involved in encoding the protein involved in this stage which inhibits the passage of the cell past the cycle's starting point through shutting of transcription of genes necessary for cell division and sequestering the proteins involved in regulation of DNA replication. Rb gene importance is evident in the fact that many common types of cancers miss both its functional copies.

Once in the growth phase, the cell can continue unchecked until the beginning of the synthesis phase. The metaphase between the growth and synthesis phase ensures that DNA is intact before replication. p53, a protein, stops the progression of the cell cycle when even the smallest DNA damage occurs. It is produced in greater quantities when the cell is exposed to DNA-damaging agents like UV and radiation rays and also induces the synthesis of a protein that inhibits the CDK-cyclin complex. Li-Fraumeni syndrome is an indication of the lack of a good copy of the Rb gene, generally characterized by propensity to develop tumors in several tissues. This is due to the cell's increased chances of producing mutation-carrying daughter cells leading to formation of tumors since without the control of p53, the cell progresses from the growth to synthesis phase regardless of damaged DNA.

Other cell cycle checkpoints are found at the second growth and mitotic transition and the mitotic phase itself. In the second growth and mitotic phase checkpoint, a failure in complete DNA replication causes specific proteins to inhibit actions of the CDK-cyclin complex by preventing their entry into the nucleus. Within the mitotic phase, cell division is not made possible until the complete movement of chromosomes to opposite poles of the cell.

The large network of proteins involved in cell cycle progression and regulation means that we are unable to fully understand details it's functioning. Intense cancer research has uncovered many genes and their respective roles in the cell cycle. Through a gradual understanding of the mechanisms underlying the cell cycle, we can hopefully find the cure for cancer.

Cancer as a multistep Process

The idea which is principal contemporary molecular world is that the development of cancer is not instantaneous but it's a complex and long genetic changes succession happening across time. The acquisition of the some traits by the precancerous cells is enabled by the changes which then create a malignant cancer cells growth. The triggering of cancer role is played by two genes categories. The cell cycle is controlled by these genes in their normal forms. This is the events sequence by which the enlargement and division of the cells takes place. Cell division is encouraged by proto-oncogenes which is one of the categories of the genes. Tumor-suppressor gene which is the other category inhibits the cell division. The organs and tissue in the body is maintained to the structure and size which meets the needs of the body by regulation of the growth which is coordinated by both tumor-suppressor and proto-oncogenes genes.

It should then be noted that oncogenes then result from the mutation of the proto-oncogenes and they are responsible for the stimulation of excessive division. These genes are inactivated by the mutations in the tumor-suppressor genes therefore the cell division inhibition is eliminated which is critical in the normal excessive growth prevention. Most of the cell division which is not controlled in the human cancers is accounted for by the collective mutation of these genes (National Cancer Institute).

The role of oncogenes

Of importance is the role of the proto-oncogenes or more precisely the oncogenes that result from their mutations play in the cancer development. Signals involved in the growth stimulation are received and processed by molecular pathways that are coded by the proteins. A growth factor is first produced at the beginning of such signaling and this growth factor is basically a division stimulation protein. The specific receptor proteins which are found in the neighboring cell's surface is the place that the growth factor attaches to after moving through inter-cellular openings and spaces. A stimulatory signal is conveyed to the cytoplasm proteins by the receptor after a factor which is growth stimulating binds to it. Stimulatory signals are emitted by these proteins to other proteins in the cell till the nucleus of the cell receives the message promoting division and then a set of genes which aid the cell movement through its growth cycle is are activated (National Cancer Institute).

The growth promoting pathways protein is caused to be overactive by the oncogenes which is the mutated form of the proto-oncogenes. Therefore there is a faster proliferation of the cells than if the mutation had not occurred. The growth factors overproduction in the cells is caused by some oncogenes. The neighbor cells growth is stimulated by these factors but the excessive cells division of the cells which produced them may also be caused by them. Deviant receptor proteins are produced by other oncogenes and these ones are responsible for the stimulatory signals release into the cytoplasm even with the absence of the growth factors in the environment. Still the signal cascade occurring in the cytoplasm of the cells is disrupted by some oncogenes such that a stimulatory message is received incessantly by the nucleus of the cell even when there is no prompting from the growth factors.

The role of tumor-suppressor genes

There must be disentanglement of the cells from the messages which are inhibitory so as the cells can be cancerous since they are involved in the counterbalancing of the pathways which stimulate the growth. Just like the stimulatory messages, inhibitory messages in the normal cells flow to the nucleus of the cells. The inhibitory messages which are usually powerful normally can be ignored by the cell if the flow is interrupted.

Most of the known tumor suppressor's normal functions are still being investigated by the scientists. The coding of proteins whose operations are part of the inhibitory specific pathway parts is done by some genes. Normal functioning of the inhibitory pathway is hindered if the proteins are caused by the mutations to be absent or inactive. The signal flow seems to be blocked by some tumor-suppressors genes through the growth stimulating pathways; there can be no restraint in the growth promoting pathways when the proper functioning of these genes is not present. The vital tumor suppressor's proteins are inactivated by mutations in all the genes of the tumor suppressors and this deprives the cell division restraint of the cells.

The body's back-up systems

There are other three systems which aids in the prevention of the runaway cell division in addition to the proliferation control afforded by the tumor suppressors and proto-oncogenes coordinated action. The DNA system repair is the first one of the systems. The errors are detected and corrected in the DNA by this system which operates in almost all body cells. The carcinogens from the cellular produced chemicals and those gotten from the environment are constantly attacking the genes of the person across his lifetime. The DNA replication also does have error occurrence. The DNA repair system of the cell is the one responsible for most of its rapid correction. The error which is now a mutation becomes a permanent feature present in the cell and its subsequent descendants. The reason for the usually many years that must pass before the occurrence of all the mutations needed for development of cancer to occur in one cell is due to the usually high efficiency of the system. The genes are repaired by themselves in the DNA mutations however this repair system can be undermined in specifically devastating manner. The cell's error repairing ability is damaged in the DNA. Therefore there is a high frequency of mutations to appear in the cells consisting of those in cell growth control by genes (Michor F, & Nowak, 2004, p.199).

The other back-up system in the cells causes the cell to commit suicide usually referred to as apoptosis when vital parts of the cells are damaged or there is deregulation of the control system. Therefore the cells which manage to evade such deaths develop into tumor. The p53 is one of the ways involved in the avoiding of apoptosis. The cell division only is halted by this protein in its normal form, but apoptosis is induced in the abnormal cells. In many cancer types, p53 is inactivated and it's tumor-suppressor gene product. The cancer patients are endangered in two ways due to the ability to avoid apoptosis. First the tumor growth is contributed by it and secondly the resistance to treatment of cancer cells is caused by this. The thought that cancer cells were being killed directly through chemotherapeutic drugs and radiation by harming of their DNA was held by scientists. However it is now clear that the DNA cells are damaged slightly by such therapy and the damaged cells kill themselves actively in response. There is the suggestion from this discovery that evasion of apoptosis by the cancer cells will make them not as responsive to treatment as other cells are. The last back-up system ensures there is no endless reproduction of the cells by limiting the cell division number of times. The DNA segments at chromosomes ends are involved in the counting mechanism which governs this system. Each time a chromosome replicates, the segment shorten and they are referred to as telomeres. An internal signal which causes cell division to stop is triggered when the telomeres are shorter than the threshold length. Further telomeres shortening takes place if the cells continue to divide and causes the chromosomes to eventually break apart or get fused to another and this is a fatal genetic crisis to the cell.

The cancer cells have been observed during their culture growth that they can proliferate indefinitely unlike the normal cells. It has been discovered by the scientists recently that this characteristic molecular basis telomeras which is an enzyme that replaces systematically the telomeric segments which during the cell division gets trimmed away. Most mature cells do not have the telomerase most cancer cells have it whereby the endless proliferation of the cancer cells is enabled by it.

The multistep development of cancer

The development of cancer isn't once as a major cellular functions shift caused by the mutations from various aberrant genes. On the contrary, it's a step-by-step development over time signifying many molecular changes accumulation with the characteristic which produce the malignant state being contributed for by each change. There can be very large number of cell division occurring during the process and the apparent manifestation of the human tumors is when they have grown to sizes of billions of cells. The time frame involved is also considerable long taking decades normally to attain the malignant state through enough mutation accumulation. A number of long standing observations can be explained by the multistep understanding of cancer which occurs over time. The incidence increase with age is a key observation. In most cases the experiencing of extended and complex succession of events by people who have lived long enough leads to them experiencing the disease. This is because each change is usually not common but a rare accident which needs years to occur, and a long time is required by the whole process and most people die due to other causes before the whole process of cancer development is complete (Lodish, 2004, p.93).

The incrementing of incidences of cancer in people who have been exposed to carcinogens is well explained by this way of understanding cancer. This also includes inheritance of predisposing mutations by people which also increases their cancer risk. The likelihood that a certain harmful changes will occur is increased by the carcinogens exposure and the probability of developing cancer during normal life span is increased. Again the mutations are no longer a rare event but it would have occurred in the case of inheritance of mutation which is cancer-susceptible and this is not in a single but all the cells in the body. Therefore there is a leap-frog in the tumor formation process. Therefore the changes which will be necessary to attain malignant state accumulation may happen in one or two decades instead of the usual several. The lag time that is credited for separation of the cancer causing agents exposure and the cancer development. For instance the development of skin cancer several decades after having grave sunburns in children can be explained by this understanding. The 20 to 25-year lag that was evident between the increased cigarette smoking after World War II in women and the huge increase of incidences of lung cancer which occurred in the 1970s among women.

Apoptosis in health and disease

During the normal multi-cellular organism development there is the occurrence of apoptosis and it goes on throughout the life of the adult. The shaping of organs and tissues in the embryos which are developing is dependent on the cell proliferation and apoptosis combination. For instance the separation of the toes is due to the cells apoptosis located between the toes. An important component of the immune system regulation is apoptosis. The damaged and infected cells are destroyed by the immune system T. lymphocytes cells in the body. Thymus is there maturity area and they are tested before they are allowed to enter the blood system to ensure they are not reactive towards cells which are normal and healthy and for their efficiency against foreign antigens. By the apoptosis induction, the self reactive or ineffective T-cells are removed (Henkart, 1999).

There have been implications of the apoptosis regulation problems in several diseases. Little apoptosis is the characterization of cancer disease. A number of mutations are present in the cancer cells and this makes contribute to the ignoring of the normal cellular signals which are responsible for the regulation of their growth and they deviate from the normal form to become more proliferative. Apoptosis is undergone during the normal circumstances by the damaged cells but apoptosis might be inhibited in cancer cells by the mutations might have occurred. The disease progresses to tumor formation because the cellular proliferation is not checked. Because many cancer treatment depend on the cells being damaged by chemicals and radiations and resistant cells are produced by apoptotic pathway mutations, the tumor are not easily killed.

Angiogenesis

Angiogenesis it the growth of new blood vessels and it plays a principal role during the cancer onset and progression and thus vessel growth inhibition can be exploited for metastasis and tumor growth control. This inhibition is important concept in the cancer therapies which are efficient design. Of importance is the understanding of the molecular mechanism which govern the vascular differentiation and growth and how they are significant to the tumor expansion. Tumor vascularization studies have produced some observations which has indicated that numerous signaling pathways used in embroyo vascularization is reactivated by the pathological blood vessels. Additional mechanisms which don't operate in the embryo can be the basis for pathological vascularization. The vasculature is a conduit which is flexible used for exchange and delivery of nutrients, hormones, wastes and immune cells. The heart and the blood vessels are usually the first identifiable organ system to be developed. Blood vessels network incessant maintenance and maturation is vital for homeostasis and tissue metabolism as well as processes of repair such as wound healing and inflammation

Cancer onset and progression is centrally affected by the role of vascular growth. There are two constituents for the blood vessels i.e. The mural cells and the endothelium. Endothelium is cylindrical sheet of epithelial which is continuous and is involved in the vessel lumen creation. The non-thrombogenic surface is maintained by the endothelial cells which interface with the blood directly. The contractile mural cells which is the second vessels component, is separated from the endothelium by a basal lamina. The endothelial tube is surrounded by these cells which are principally responsible for vascular tone modulation. The mural cells in large caliber vessels like veins, arteries, venules and arterioles are referred to as smooth muscles and their organization is in multiple layers of the cells. The endothelium is surrounded by a single cell layer called pericytes at the microvasculature layer consisting of post capillary venules and capillaries. The vascular growth and physiology is contributed by the heterotypic and homotypic communication between the mural cells and the endothelium (Lodish, 2004, 184).

An extreme example of quiescent, stable cell population of cells is represented by the vasculature in the adults with about 1000 days for the turnover time of the endothelial cell of the adult capillary. Tissues that is highly regenerative like the gut epithelium in contrast has an average turnover of 2-3 days. Specific psychological stimuli is the one responsible for new blood vessels growth in adults for instance the chronic tissue metabolism increases and during female reproductive cycle which causes hormonal fluctuations and this causes the growth of new vessels stimulations. There is rapid growth of blood vessels in the developing embryo tissues which is in contrast to the adult life. Two blood vessels growth mechanism which are well-known operation are the angiogenesis and vasculogenesis. The blood vessels de novo formation is entailed in vasculogenesis from the precursors of the endothelial cells or the angioblasts that are derived from mesenchyme and this one is primitive. The major axial vessels like aorta mode of development are vasculogenesis in the embryo and also for vascular plexus of organs which are derived from the endoderm such as the spleen. New blood vessels formation is involved in angiogenesis from pre-existing vessels sprouting. In the embryo neural vascularization and mesodermal tissues for instance the limb and brain bud, this is not its only mechanism but also for adult tissues neovasclularization. The blood vessels are remodeled excessively and this occurs in parallel or subsequent to angiogenic sprouting network formation so as the vessel caliber can be modified through fusion or network properties change through vessel segments selective regression or anastamosis.

Infectious cancer cells

Carcinogenesis is the process where oncogenes, are activated by cellular mutations resulting in transformation of normal cells into tumor cells. Therefore, a tumor is a result of a process starting in its individual host and ending with either its elimination or the host's death. Two recent studies suggest however, that tumor cells can act like infectious agents by moving from one host to another (Murgia, et al., 2006, p.504).

Canine transmissible venereal tumor (CTVT) has been suspected to be transferred between dogs by tumor cells implanting themselves from donor to recipient and then grow as allograft. This hypothesis is evidently supported indirectly by the tumor only being induced by the implantation of whole tumor cells, not by cell extracts of dead cells. Normal canine cells comprise 78 chromosomes but karyotypes of tumor cells, isolated from different animals show a characteristic, persistent aneuploidy pattern with58 to 59 chromosomes. Adding to this is the presence of a LINE-1 insertion close to c-myc present in all tumor samples. If this hypothesis is correct, an animal's tumor cells should be genetically clustered and different from normal cells of a host animal (Dingli, & Nowak, 2009, p.35).

Claudio Murgia and Robin Weiss's colleagues have been able to formally prove this hypothesis. They studied tumor and normal cells isolated from dogs, from three different continents, harboring CTVT. They proved that all tumors are closely related genetically and different from the host dog's normal cells by combining dog leukocyte antigen (DLA), microsatellite DNA and mitochondrial DNA sequencing. Tumors from different animals had less variability than what is observed within the most inbred breeds of dogs, as was shown through sequencing of microsatellite DNA regions. Tumors cannot arise from separate cell transformations within the animal, but were transmitted from a dog to another, thereby confirming the tumors spread from an ancestral clone. By comparing tumor and various canine microsatellite markers, it was estimated that the clone arose between 250 and 2500 years thus making it the oldest known continuously replicating somatic cell line (Murgia, et al. 2006, p. 507). Pearse and Swift, in an independent study, reported that horizontal tumor cell transmission between Tasmanian devils caused devil facial tumor disease. Cancer cells isolated from different animals harboring tumors of different age and size, share the same aneuploid karyotype. Further proof of tumors not arising from host cells was shown when it was found that one animal had a constitutional pericentric inversion of chromosome 5, an abnormality not found in any of the cells isolated from the tumor.

The ability of tumor cells behaving like infectious agents in animals raises questions of occurrence of infectious transmission of cancer in humans. As at now, there is no evidence of direct horizontal transmission of tumor cells between humans with normal social contact. Pregnancy is the only known physiological route of transmitting tumor cells in humans. About 3,500 pregnant women in the United States have concomitant malignancy each year. There have been observed cases of trans-placental transmission of lymphoma, acute leukemia, melanoma and carcinoma from mother to fetus. In cases where the mother has a multiple pregnancy, development of acute leukemia in both fetuses has been due to the transfer of acute leukemia cells through their transfer between them.

Another possible route of tumor cell transmission in humans is organ transplantation due to the compromise of one's immune surveillance due to immunosuppressive therapy so as to ensure survival of transplanted organs. This in turn facilitates engraftment and growth of donor derived tumor cells. Donor derived tumors in solid organ transplant recipients is however rare occurring on about 0.04%. Malignant melanoma goes undetected in a donor with occult disease, making the recipient susceptible to developing the disease. Hematological malignancy by hematopoietic stem cell transplantation is also another example with a 0.06% frequency. There has been a reported case where a surgeon developed malignant fibrous histiocytoma after accidentally injuring his palm in the process of surgically removing the tumor from a patient.

Transfer of tumor cells between individuals seems rare in humans. A factor contributing to this is the difference in the human lymphocyte antigens protecting against successful tumor cell engraftment through inducing an immune response eliminating the implanted cells. Down-regulating of DLA expression enables CTVT cells avoid immune mediated destruction. This makes it an important adaptation as complete absence of DLA antigens would create room for natural killer cells to destroy the tumor, while, if expressed normally, DLA antigens activates cytotoxic T-cells with a similar outcome. An immune attack against CTVT in many dogs develops and leads to tumor eradication and immunity re-challenge. This further strengthens the hope of the possibility of coaching the immune system to eradicate established tumors in humans (Dingli, & Nowak, 2009, p.35).

Cooperation between cells of a given organism is required in order to facilitate emergence of multi-cellular life forms. Cancer becomes a 'defector' from the evolutionary game theory perspective as it requires loss of the above stated cellular cooperation. In breaking down of the cooperation, the tumor meets its own demise but as a result of the host's death. This means that, a tumor that can be transmitted from a host to the next, maneuvers around the evolutionary mechanism meant to control it.

The main reason as to why cancer is generally not transmissible between people is by MHC incompatibility causing tissue graft rejection. The donor's cancer cells should be able to induce a vigorous response in a healthy recipient. In mice, tumor transfer is possible between animals sharing the same MHC, or if the case of the recipient being severely immunosuppressed. This leads to the speculation that the main reason for diversity in MHC in humans and other vertebrates ensures that cancer is not an infectious disease as Murgia et al. suggested.

Genetic instability in cancer

Genetic instability is the events sets in the genome that can cause unplanned alterations which are either permanent or temporary in nature. The diverse genetic changes are encompassed by this term of which a variety of ways can be used in their classification. Two major groups can be used to classify them for simplicity depending on where the instability occurs i.e. instability at the nucleotide level and that at the chromosomal level (Perera & Bapat, 2007). Faulty repair of the DNA can cause occurrence of the nucleotide level instability for instance the nucleotide excision repair and base excision repair and the microsatellite repeat sequence instability is included caused by mismatch defects repair pathway. Chromosomal instability is the second form and the accelerated rate of chromosomal alterations are defined by this existence and this leads whole chromosomes losses and gains together with deletions, inversions, translocation and duplications of huge segments of chromosomes. Abnormal karyotype also referred to as aneuploidy is many cancer cells hallmark and its development is believed to be due to CIN. The harbouring of several abnormal chromosomes observation was made about a century ago and ever since the understanding of this kind of instability has come a long way. There have been implication of various pathways in the CIN consisting of checkpoint of the cell cycle pathways and kinases; centromere and telomere stability pathways, post translation modifications regulating pathways, chromosome segregation and cohesion of sister chromatid and duplication of centrosome.

Cancer stem cells and Genetic instability

There has been rapid growth in popularity of the carcinogenesis stem cell model. The cancer stem cell has been defined as a cell in the tumor with self-renew capacity and therefore the heterogeneous lineage arises of which constitutes the tumor. The development of the cancer cells can results from stem cells in the tissue which have undergone mutations making them cancerous. Or there may be more differentiation of properties that are characteristic to the stem cells as a result of mutations. The stochastic carcinogenesis model that is also widely accepted is different from either scenario. There has been identification of stem cell of the cancer or cells which initiates cancer in breast tumors, acute myelegenous leukemia and brain tumors. The important questions which have arisen from the discovery of cancer initiating cells existence with regards to the existence of genetic instability in these cells and the role played in these cells (Perera & Bapat, 2007).

The greater level of epigenetic and genetic changes is caused by the endogenous and exogenous environmental agents in the stem cells as opposed to their counter parts which are differentiated and have short life span by their very definition. There is need for more research to be undertaken because it is a fairly new field so that the relationship between cancer stem cells and genetic instability can be determined. Work from telomere instability and haematological malignancies have provided some preliminary evidence. There can be division of the Haematological neoplasia into three stages of acute, chronic and premalignant with the most advanced stage being the first one. During the chronic myeloid leukemia progression, telomere loss was shown to be more rapid and patients in the early chronic phase had longer telomeres than patients in late chronic phase. Additionally there were more cytogenetic abnormalities in the patients with pre-malignant disease whose telomeres were shorter and also the increased leukemia transformation saw the prognosis to be poorer. The idea the genetic instability in the stem cells can be due to the shortening of telomeres is suggested by these studies and this is also supported by that fact that the shortening of telomere is during the early period of carcinogenic cascade and this indicates the probability that this process happens in the cancer stem cells. In addition the pre-malignant progression of the disease to acute stage correlated with the activation of telomerase. Telomerase reactivation and attrition are the risk factors which are implicated by these observations for the stem cells malignant transformation (Perera & Bapat, 2007).

Conclusion

Cancer is an intricate disease with several multiple genes with its initiation, invasion, progression and metastasis involving diverse pathways. It is accepted widely that mutations accumulation which happen sequentially, activates oncogenes while making the tumor suppressors genes to be disrupted in combination with several clonal selection cycles and the process of carcinogenesis is facilitated by evolution. This transformation has been estimated to require the disruption of almost six cellular processes. This number has however been hinted to be higher after the evaluation of breast and colon cancer genomes than it has been estimated previously. The limiting rate in the carcinorgenensis process steps would then be the rate which the occurrence of mutations it if this model is true and the carcinogenesis rate should be affected by any factor that this rate is influenced by.