Cancer is the abnormal proliferation and differentiation of cells in an abnormal tissue incongruent with the growth pattern of normal cells that persists even after the stimuli that evoked the change is withdrawn. The cell cycle check points at G1, G2 and at the end of metaphase that prevent transmission of genetically damaged DNA fail to occur. Transmission of faulty DNA results in either an abnormal rate of cell division and multiplication or abnormally constituted daughter cells.
The genes affected are the normal regulatory genes including growth promoting proto-oncogenes-normal genes that are prone to becoming cancerous on mutation or over expression, growth inhibiting tumor suppressor genes that suppress proliferation of cancerous cells, genes involved in apoptosis responsible for the ‘death’ of detected abnormal cells and genes involved in the DNA repair of the abnormal cells.
The causes of the genetic damage are varied and could be hereditary thus predisposing one to risk e.g. in breast cancer. It could also be due to environmental factors (carcinogens). These include radiation, virusese.g. human papilloma virus responsible for cervical cancer and chemical agents in alcohol, nitrites, nicotine and cytotoxic drugs. Trauma and burns could also progress to cancer.
Genomic flexibility is limited by the check points in the cell cycle during selection. The G2-M checks for any genetic defects and ensures gene repair or apoptosis prior to chromosomal replicationwhile G1-S checkpoint ensures the ‘environment’ is conducive for replication thus avoiding carcinogens. These boundaries are necessary for cancer survival as alterations in regulatory genes allow for abnormal cells to proceed to mitosis without detection. The karyotypic properties that allow this include the ability of karyotypes to rearrange themselves into cancerous karyotypes. This rearrangement results in an imbalance of the mitosis genes that destabilizes the karyotype. This destabilization however allows for heterogeneity in cancers that imparts flexibility to the karyotype.
Cancer cells are in effect immortal due to their uninhibited proliferation. This is autonomy is a result of several factors. During normal cell growth, growth factors bind to receptors on the cell membrane to form a growth factor complex. The formation of this complex results in a transient activation of signal transduction proteins and pathways in the cell cytosol. The signals are then transmitted to the nucleus by second messengers. This results in the induction and activation of nuclear regulation factors that initiate the cell cycle that is controlled by cyclins and cyclin dependent kinases that ensure progression from one stage to another through the checkpoints resulting finally in cell division.
Cancerous cells attain autonomy by bypassing each of these processes. These cells produce their own growth factors and production persists even in the presence of inhibitory signals. Or they induce stromal cells (tissue that provides nutrition and support to cancerous cells including blood and lymphatic vessels) to produce the growth factors. This is coupled by over expression of receptors on the cell membrane allowing for complex formation at a higher rate than normal cells. Receptors could also mutate resulting in hyper responses even in the presence of low levels of growth factors. This results in amplification of signal transduction activating the second messengers. Normally second messengers are degraded after signal transduction but in cancerous cells, degradation is inhibited resulting in higher levels and faster signal transduction. Protooncogenes that encode signaling pathways transmitting signals to second messengers including the G protein RAS and tyrosine kinase ABL undergo mutation. This leads to an inappropriate continuous stimulation insensitive to inhibitory signals that increases expression of growth promoting genes that drive the whole cycle as they initiate synthesis of growth factors. Cyclins and cyclin dependent kinases including p21, p27 and p57 control check points in the cell cycle and do not allow progression until damaged DNA is ‘killed’ or repaired. Cancerous cells increase the synthesis of cyclin dependent kinase inhibitors that allow for progression of cell division despite mutations in DNA. Tumor suppressor genes produce inhibitory signals that inhibit excessive cyclins, cyclin dependent kinases, second messengers, cell membrane receptors and nuclear regulation factors in normal cells preventing hyper expression by ensuring activation is transient. However, cancerous cells are insensitive to growth inhibitory signals.
The speciation theory postulates that karyotypic alterations induce cancer in normal cells while the mutation theory holds that 3- 6 mutations in a cell render it cancerous. The mutation theory argues that the karyotypic alterations are consequences of cancer rather than the cause. The sum total of the mutations results in the karyotypic alteration. The alteration is random and not in all cells. The theory adds that cancer chromosomes are unstable. However, studies on the Tasmanian devil have shown that karyotypic alterations are clonal and stable since they are transmissible between generations. It thus follows that they are a cause of cancer rather than a consequence. This is supported by the individuality of karyotypes that corresponds to individual cancers.
I therefore think that the speciation theory is more plausible than the mutation theory. Mutations aremore likely to be corrected by regulatory genes and the cell cycle checkpoints than karyotype alteration that involve the complete set of chromosomes.
Works Cited
Duesberg, R., et al. "Is carcinogenesis a form of speciation?" Cell cycle 10.4161 (2011): 2100-2114.
Kumar, Vinay, et al. Robbins Basic Pathology. New York: Elsevier Health Sciences, 2010.
Marx, J. "Debate surges over the origins of genomic defects in cancer." Science 297.5581 (2002): 544-546.
Vincent, MD. "Cancer: beyond speciation." Advanced Cancer Research 112 (2011): 283-350.
Weinberg, Robert A. The Biology of Cancer. London,UK: Taylor & Francis Group, 2011.
