Cancer Pathophysiology Free-Samples for Students-Myassignment

Question: Your task is to Describe how a Cell goes from Developing Cancerous Mutations to actually moving to new Sites in the Body. Answer: Biochemistry of cancer The emergence of cancer cells can be traced back to the cell cycle. According to Park, M. T., Lee, S. J (2003) a cell undergoes the interphase and the mitotic phase. In the interphase the cell grows and makes a copy of its DNA while in the mitotic phase the cell separates the DNA into two sets. The interphase includes the three stages that occur before the mitosis phase, that is, G1, S and G2 phase. The cell cycle events occur sequentially in the four stages. During the two gap phases, G1 and G2, the cell undertake active metabolism without any form of division. In synthesis(S) phase, the chromosomes duplicate as a result of DNA replication forming two copies of identical genetic material. During the mitosis phase, the chromosomes separate in the nucleus and the division of the cytoplasm and the organelles occurs. Checkpoints in the cycle at the end of G1 and G2 that can prevent the cell form entering the S or M phases of the cycle .Mutations in proto-oncogenes or in tumor suppresso r genes allow cancer cell to grow and divide without the regulation which is normally done within the cell cycle. Image credit:"The cell cycle: Figure 1"by OpenStax College, Biology (CC BY 3.0). The P53 protein is one of the genes that regulate this process of replication. It is a transcription factor which binds the DNA and activates the transcription of protein p 21. This protein inhibits the activity of a cycline dependent kinase required to enter G1 phase. This particular action allows time for the repair of the genetic material. A mutation that occurs either induced or occurring naturally may lead to formation of cancerous cells since the regulation step is not present. Other proteins involved in tumor suppression besides p53 are p16 and pRB. T work by inhibiting they all work by inhibiting cycline dependent kinases Differentiation Cell differentiation refers to the process through which developing cells mature and become specialized to carry out a particular function in the body. Differentiation is regulated by signals which promote maturation of the cells. In the case of cancer, there is differential differentiation of cells. The much differentiated cells look like the mature normal body cells. The progression of this tumor is usually slow. There are poorly or undifferentiated cells. These can be attributed to failure of response to the differentiation signal. Consequently, they tend to grow very fast. The differentiation of the cells is used to grade tumors into four grades. These are: undetermined grade, low grade, intermediate grade and high grade. Transformation According to the national cancer institute, transformation refers to the process through which cell undergo change and become malignant. Malignancy refers to uncontrolled cell division which has a potentiality of bringing about invasion of the nearby tissues. These cells can also invade other organs by being transported through blood vessels and lymph vessels. The key proteins involved are the tumor suppressor genes: p53 and pRB. Malignant transformation may be caused by diet, chemicals, heavy metals or infections. All these causative agents interfere with the genomic component of the cell. This has profound effects on the particular genes that suppress tumor formation. For stance in human papilloma virus infection, the viral gene E6 inhibits P53 while E7 inhibits pRB gene. In other cases mutation of these genes occurs. According to Hanahan A. Weinberg (2011), the hallmark of cancer consists of six biological changes that are acquired and important for tumor growth. They include: the acquisition of self-sufficiency in growth signals, loss of sensitivity to anti-growth factors, loss of capacity of apoptosis and senescence, sustained angiogenesis, ability to invade neighboring tissues and metastases. These changes are for classical carcinomas since not all tumors may achieve all of them. These biological characteristics are important since they enable it achieve uncontrolled growth with the ability to nourish and invade the tissues. According to clonal selection, mutant cells compete for resources in their micro environment. A clone with a tumor suppressor gene will expand only in a neoplasm were the mutation confers with an advantage over the other clones and the normal cells. Intravasation Intravasation refers to the process through which tumor cells enter the blood or lymph vessels and are thereby metastasized to other areas of the body. These cells move by a process known as diapedesis or trans-endothelial migration since the cells migrate between the junctions of the endothelial cells that constitute the wall of the vessels. Cadherin and adhesins are disrupted during this migration. Intravasation can be divided into active and passive. This classification is based on how it enters the blood stream either directly through a blood vessel or indirectly through a lymph vessel.in active Intravasation the tumor cells use a mechanism similar to that used by immune cells. They respond to chemokines, growth factors and nutrient gradient. Tumor associated macrophages release some of these molecules hence facilitating Intravasation into the blood stream. These molecules include chemokines and pro inflammatory factors. Chemokines aid in chemotaxis towards the blood vessel while the pro inflammatory factors enhance the penetration. The pro inflammatory factors are initially produced in areas around the tumor mass due to hypoxia hence used to counter oxygen deficit by increasing blood vessel permeability. Tumor associated macrophages are also involved in the process of remodeling the matrix surrounding the inflamed tumor sites. This remodeling is crucial in enabling the tumor cells migrate towards the blood vessels and access sites of endothelial wall of the blood vessel where they can invade. This remodeling also significantly affects the pericytes thereby interferes with the integrity of blood vessel wall. A series of interactions occurs between the tumor cells and the stromal cells hence they are able to enter the blood circulation. Extravasation This refers to the process by which cancer cells leave the blood stream and enter a secondary organ where they replicate. This leads to the formation of a secondary tumor in distant organs. Extravasation occurs in three steps. In the first step, tumor cells loosely attach to the endothelial cells of the blood vessels. This consequently results in a rolling motion of the tumor cells on the vascular surface this considerably lowers the movement of the tumor cells since the speed of blood at the periphery is lower than that of blood at the center. The tumor cells have a ligand which binds onto the E selectin on the endothelial cells. In the second step the tumor cells tightly attach onto the endothelial cells. This process can be referred to as adhesion. There is a change in the receptors for those used for the loose attachment and those used for tight attachment. Tight attachment is mediated by integrin activated by chemokine signaling. N Cadherin is expressed both in the tumor cell an d endothelial cells and is important in the final step which is diapedesis. Leucocyte acts as a liker cell linking the tumor through the ICAM 1 which then links to the endothelial cell. Angiogenesis Angiogenesis refers to the formation of new blood vessels. This process involves the migration growth and differentiation of endothelial cells to form new blood vessels to supply the tumor cell. This process is normally regulated by chemical signals produced in the body. Some signals activate this process while other inhibits it. According to M.E.Eichhorn, M.K.Angele C.J.Bruns (2007, Pp. 371379), the balance between the pro angiogenesis genes and anti-angiogenesis genes is upset and thereby promoting angiogenesis. The acquisition of angiogenic phenotype by the tumor cell is an important for tumor progression. Oncogene-derived protein expression and some cellular stress factors, such as hypoxia, low pH, nutrient deprivation, or inducers of reactive oxygen species (ROS), are important stimuli of angiogenic signaling. The factors involved in this process are listed below. Tumor angiogenic factors bind onto receptors on the endothelial cells and initiate a series of activities that promote angiogenesis. It involves migration proliferation and differentiation into new blood vessels endothelial cells release heparanase which digests the basement membrane and allow more angiogenic factors to reach them. The blood vessels spread without organization and the vessels have altered diameters and failure to differentiate. A vascularized tumor has a very high capability of growth and differentiation due to the presence of the necessary nutrients and oxygen for their growth. A non-vascularized tumor can only grow to about 1-2 cubic millimeters. The dependence on diffusion cannot sustain the nourishment requirement of the tumor cells. Migration Cancer cell migration is the process through which cancer metastasizes from the original tumor to other body organs. Cancer cells migrate by degrading the surrounding extra cellular matrix. They follow a leader cancer cell. The cancer cell loses cell-cell adhesion capacity and this allows the cell to dissociate from the primary tumor. The enzymes produced to disintegrate the matrix allow the movement of tumor cell towards the blood vessels. The chemokines attract the tumor cell towards the blood vessels or lymph vessel. They enter the vessels by diapedesis Circulation Cancer cells in the blood circulation express cytokeratins which indicates they are of somatic origin.in the blood stream they have to evade the immune mechanisms of the body. The tumor cells bind coagulation factors on the platelets. This forms an embolus aggregate that protects the tumor cells from by immune cells. This also protects them from shear and turbulence hence enhancing their survival. The tumor cells also activate the coagulation cascade and formation of platelet rich thrombi around the cells. Invasion This refers to the process through which tumor invades body tissues this process involves a series of proteins such as integrin, laminin and fibronectin for attachment. Enzymes are used for matrix degradation while Autocrine Motility Factor aid in locomotion. According to the three step theory of invasion, there are three particular steps: tumor attachment, degradation and dissolution of the matrix and the locomotion into the matrix. Attachment is mediated by the tumor cell plasma membrane receptors.it includes the fibronectin and laminin. In the matrix degradation, the tumor cell produces enzymes which outbalance the natural proteases in the matrix. Locomotion is influenced chemotactic factors such as Autocrine Motility Factor. Invasion takes place as a cyclic repetition of the three stages. References Gupta GP, Massagu J. Cancer metastasis: building a framework. Cell 2006 Nov 17; 127(4): 679- 95. Colotta, F., Allavena, P., Sica, A., Garlanda, C., Mantovani, A. (2009). 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