The Role of Oncogenes in Sustaining Proliferative Signalling, One of the Hallmarks of Cancer - Coursework Example

The Role of Oncogenes in Sustaining Proliferative Signalling, One of the Hallmarks of Cancer Cancerous cellular growth has been associated with an uncontrolled division and multiplication of damaged cells, which has been traced to any of the following: mutation and activation of proto-oncogenes into highly-active oncogenes; entry of viral oncogenes into the genome and inducing transformations of normal cells to cancer cells; and the silent mutation or repression of tumour-suppressing genes (Schober and Fuchs, 2011). All three mechanisms of uncontrolled cellular multiplication and growth are tied with the lack of cellular apoptosis and homeostasis among the cells, both of which are considered to be hallmarks of cancer. However, the mechanisms of tumour growth as the result of proto-oncogene mutations into active oncogenes will be given greater emphasis in this paper since under normal circumstances these genes are considered to be important in cell growth regulation during the cell cycle, thus having direct impact on normal and abnormal cellular growth. Normal Functions of Proto-Oncogenes Proto-oncogenes operating under normal conditions (i.e. no mutations) usually function to encode proteins typically involved in the cell cycle. For example, in the case of the genes coding for the Ras protein superfamily, the products are normally involved in cell proliferation by preventing cell cycle arrest and migration by maintaining the integrity of cytoskeletal structures, as well as mediating cellular membrane interactions through tyrosine protein kinase receptors (Drosten, et al., 2010). Growth factors stimulate tyrosine kinase activity, leading to autophosphorylation of receptors and the recruitment of Grb2, an adaptor protein that forms a complex with another protein called Sos in order to catalyse the inactive form of Ras (GDP-bound Ras) to the active form (GTP-bound Ras), and in turn activates the Raf-MEK-MAPK cascades which allows changes in gene expression in order to perform cell cycle processes such as induction of proliferation, differentiation, or survival (Matozaki, et al., 2009). In another example, a proto-oncogene such as splicing factor SRp20 (SFRS3) regulates the expression of a transcription factor called Forkhead box transcription factor M1 (FoxM1), PLK1 and Cdc258, which in turn controls the progress of the cell cycle and cellular proliferation (Jia, Li, McCoy, Deng and Zheng, 2010). SFRS3’s functions were identified after observing that cell growth increased after its introduction into normal cells, which is accounted for by the promotion of the G2/M transition when it encodes for normal protein and cell cycle arrest when its expression is decreased. The proto-oncogene Syt is also similar to SFRS3 in the sense that it is also plays a vital role in the cell cycle by contributing to actin fibre regulation and cellular motility or migration, as well as causing lethality among embryos when it is deficient or lacking as seen in cytoskeletal breakdowns and problems in vascular branching in mouse embryonic cells(Kimura, et al., 2009). Mutation of Syt happens through a chromosomal translocation of the segment containing Syt genes into the X chromosome, causing an overproduction of actin fibres within the cytosol. The overproduction of actin fibres also trigger the release of inflammatory cytokines and chemokines that induce tumour growth through the inflammatory response pathway, which in turn can affect other neighbouring cells and cause the growth of aggressive tumours of soft cell tissues through improved mobility (Maniati, et al., 2011). Not all proto-oncogenes produce gene products which are directly involved in the cell cycle, as there are some which produce transcription factors that affect cellular differentiation through interactions with other proteins in its family. However, upon mutation of these proto-oncogenes an over-expression can lead to oncogenic transformation, especially in the presence of other proteins. The Pokemon proto-oncogene (Pox virus and zinc finger, Krüppel, erythroid myeloid ontogenic factor) is a member of the transcriptional regressor genes that normally produce gene products that interact with other proteins and promote cellular growth and repair. It was also identified to repress the expression of tumour-suppressing genes, allowing cancerous cells to grow and multiply by cellular transformationby interacting with potent oncogenes such as BCL6 and LMO2 (Maeda, et al., 2005).Thus the Pokémon proto-oncogene can only cause tumours upon the presence and cooperation with other oncogenes. Oncogene-Activation, Proliferative Signalling, Signalling Pathways and Tumour Cell Proliferation Proto-oncogene activation through various ways of mutation (genetic or epigenetic mutations) can lead to an excessive amount of gene products that normally control cell immunity, apoptosis and differentiation and are often found in cellular growth and division such as growth factors and signal-transduction proteins (Oeckinghaus, Hayden and Ghosh, 2011). While the transcription of these proteins are usually controlled by the cell cycle as well as through negative feedback mechanisms, upon genetic or epigenetic mutations it only needs one dominant allele to cause proto-oncogenes to become oncogenes by increasing the amount of gene products, known as a gain-of-function mutation (Matoki, et al., 2009). This in turn leads to positive feedback mechanisms which increase gene products and in turn contribute to a prolonged proliferation of cells leading to increase in cell growth and mass as well as increased vascularisation within the cancerous cells, allowing the increased nutrient intake within the cancerous cells which again then leads to increase in cell growth and mass, and so on (Bottos and Bardelli, 2013).These excessive gene products that cause increased tumour masses are exhibited through a more aggressive cellular migration, invasion, and transformation by the increase in proteins needed for cell growth. Genes that encode dual-function transactivator-phosphatase proteins such as the Eyes Absent (EYA) genes regulate eye and muscle development as well as DNA damage repair, but can promote tumorigenesis and metastasis of cancerous cells through increased EYA phosphatase activity (Pandey, et al., 2010). Cell motility was observed to increase in the over-expression of the EYA genes Eya2 and Eya3due to over-expression of the C-terminal tyrosine phosphatase domain in Eya3’s domain, with the transactivation of the proteins causing a miss-deployment of cell-fate determination allowing a further proliferation of the cell cycle though an increase in the release of regulatory proteins cyclin D1 and A1, as well as the proto-oncogene c-Myc. The phosphorylation state of proteins was also affected by promoting actin cytoskeleton structure, in turn allowing increased lamellipodia and filopodia production in cells (Pandey, et al., 2010).An increase in motility structures and gene productssupports the increase and growth of motile cancerous cells, eventually allowing these to metastasise into other structures through angiogenesis. Not all genetic mutations cause proto-oncogenes to become active oncogenes, as epigenetic mutations such as the introduction of mutagens and other post-transcriptional modifications can trigger oncogenetic activity. An example of this is the effects of reactive oxygen species (ROS) to certain transcription factor proteins, which increase oncogenic gene expression and in turn, increase in protein functions. In usual cases of genes coding for transcription factorproteins, there is always a repressor protein interacting to prevent over-expression of the genes. However, it has been identified the metabolism and detoxification of mutagens such as ROS can affect repressor proteins negatively such as Keap1, and allow increased expression of oncogenessuch as Nrf2 through signalling, enhancing its activity in the absence of its repressor protein and promoting tumorigenesis(DeNicola, et al., 2011).Under normal conditions Nrf2 is repressed in order to allow cell senescence and reduction of intracellular ROS through the release of K-RasG12D gene products however any disruption to its protein release causes elevated levels of ROS and Nrf2 protein activity. This in turn reduces immunoreactivity of other gene products, allowing the expression of oncogenes such as B-RafV619E that lead to tumour growth such as human preinvasive pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA)(DeNicola, et al., 2011). Altered metabolism can also signal the presence of cancerous cells, as it has been found that tumours have higher rates of glycolysis, lactate production, and endogenous lipid biosynthesis, resulting to de-novo synthesis of fatty acids and other extracellular lipids (Fritz, et al., 2010).Oncogenic signalling can come as a result of the production of the extracellular excess fatty acids through positive feedback mechanisms, wherein due to the need for increased signalling of cell growth receptors and generating signalling molecules, cancer cells synthesise new membranes and trigger cancer cell growth and survival by undergoing de-novofatty acid synthesis, usually relying on Ras-mediated transformation via lipid synthesis pathways (Fritz, et al., 2010). Oncogene mutations are not the sole causes of cancer development, but it is also possible that the activation of embryonic genes can cause tumourigenesis, as in the case of the embryonic gene PAX3 which is usually present during the embryonic stage in contributing to diverse cell lines. It was found out through knock-down and down-regulation experiments of PAX3 cell migrations and metastasis were prevented by reducing the adhesion of cells to extracellular matrix (ECM) proteins as well as increasing cell apoptosis rates, cytoskeletal changes and other signalling pathways. PAX3 is usually switched off during terminal differentiation in neural-crest formation and nervous system development, allowing for the inhibition of persistent cell growth, G1 cell cycle arrest, apoptosis, cell migration and invasion inhibition however its re-expression can contribute to the sympathoadrenal lineage of the neural crest, eventually developing into neuroblastoma in children (Fang, et al., 2014). Oncogenes, Tumour Microenvironment (TME) and Tumour Proliferative Signalling On their own, oncogenes cannot proliferate a steady growth of cancerous cells the body still contains other mechanisms that can prevent cloning mechanisms of defective cells. It normally takes the combination of the presence of defective, proliferative cells along with the steady provision of nutrients, transformation factors, pro-invasive growth factors, hormones, and cytokines to sustain cancerous cellular growth (Pietras and Östman, 2010; Wang, et al., 2010).These factors combined creates an environment conducive for tumour growth that induces cancerous cellular growth called a tumour microenvironment (TME) and made up of cells called stroma, which is often an area surrounding a tumour growth as well as sporting smaller growths or polyps within proximity. The proliferative signalling and growth of the TME occurs as the result ofthe activation of signal transducers and activators, as well as transactivation of genes involved in the mitotic phase of the cell cycle which in turn activates signalling pathways such as B-cell receptor (BCR) pathways that mediate an increase in antiapoptopic or proliferative factors to support the growth of tumours within the area, which in the case of chronic lymphocytic leukaemia (CLL) is the increase in antigens that activate BCR pathways and the proliferation of lymphoid tissues (Herishanu, et al. 2011; Shain, et al., 2009). In addition, the presence of self-renewing cancerous cells called cancer stem cells (CSC) promote further tumour evolution by growing near the TME’s margins and facilitate in its growth, expansion, and angiogenesis by building strengthening the connections of the TME with external blood and nutrient supply (Lathia, et al., 2011).Through a positive feedback loop, this mechanism not only aids in the growth or transformation of normal cells into cancerous cells, but also allows for the growth of multiple areas of congregation. Aside from the creation of a positive feedback loop that allows the generation and growth of cancerous cells, the TME is also characterized by the remodelling and stiffening caused by the abnormal increase in actin, collagen, and other cytoskeletal elements, making tumours a lot more dense than the normal surrounding tissues (Leventhal, et al., 2009). This stiffening not only provides protection for the defective cells, but is also enhances cellular growth, survival, and even migration by allowing spaces where cells can move via cytoskeletal modifications, increase cell-to-cell adhesion, and allow collagen crosslinking to stimulate further stiffening of the TME and increase integrin expressions. Tumour associated fibroblasts (TAF), which are considered to have been derived from mesenchymal cells (MSC) also increases the conduciveness of the TME and allows for the augmentation of the tumour cells through the production of growth factors, cytokines, chemokines and matrix-degrading enzymes as well as allowing immunomodulatory mechanisms and even angiogenesis to occur within it (Spaeth, et al., 2009). 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Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. Oncogene, 29(23), pp. 3335-3348. Read More