Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Extracellular matrix wikipedia , lookup
Cytokinesis wikipedia , lookup
Cell growth wikipedia , lookup
Tissue engineering wikipedia , lookup
Cell encapsulation wikipedia , lookup
Cell culture wikipedia , lookup
Organ-on-a-chip wikipedia , lookup
Cellular differentiation wikipedia , lookup
Radiobiology Lec 2: stage 2: 2.Carcinogenesis and the Cell Cycle 2.1.Oncogenes: Genes that are mutated or synthesized in abnormally excessive amounts and easily transform normal cells into cancer cells are termed oncogenes. The development of cancer at the cellular level is termed carcinogenesis. The combination of mutations that affect biological events such as cell survival, growth control and differentiation is the basis for carcinogenesis. What is the cancer? Cancer is a disorder characterized by the continuous proliferation of cells. This event happens when the increase in the number of excessively proliferating cells is not balanced by normal cell loss. These cells continuously invade and damage the organs of organisms. This imbalance arises from both the genetic abnormalities of cancer cells and the inability of the organism to recognize and destroy these cells. Features of Cancer Cells: Tumor cells gain several phenotypic features during the development of cancer. Those changes cause the rapid and uncontrolled proliferation of tumor cells, as well as their spread to surrounding tissues. In addition, those cell scan survive independently in specific microenvironments and have the ability to metastasize. 1 Unique Features of Cancer Cells: 1. Clonal origin: Most cancer cells originate from just one abnormal cell. However, some cancers arise from more than one malign clone. These clones are formed because of either field damage (tissue cells exposed to more than one carcinogen) or heritable defects in some genes. 2. Immortality: Most normal cells can undergo a limited number of divisions. On the other hand, cancer cells can undergo an unlimited number of divisions and form endless numbers of cells. One of the mechanisms for immortality is associated with telomeres, which are the tips of chromosomes. Telomeres cap and protect the terminal ends of chromosomes. The name telomere literally means, “end part.” Mammalian telomeres consist of long arrays of TTAGGG repeats that range in total length anywhere from 1.5 to 150 kilobases. Each time a normal somatic cell divides; telomeric DNA is lost from the lagging strand because DNA polymerase cannot synthesize new DNA in the absence of an RNA primer. Successive divisions lead to progressive shortening, and after 40 to 60 divisions, the telomeres in human cells are shortened dramatically, so that vital DNA sequences begin to be lost. At this point, the cell cannot divide further and undergoes senescence. Telomere length has been described as the “molecular clock” or generational clock because it shortens with age in somatic tissue cells during adult life. Stem cells in self- renewing tissues and cancer cells in particular, avoid this problem of aging by activating the enzyme telomerase. Telomerase is a reverse transcriptase that includes the complementary sequence to the TTAGGG repeats and so continually rebuilds the chromosome ends to offset the degradation that 2 occurs with each division. Virtually all human tumor cell lines and approximately 90% of human cancer biopsy specimens exhibit telomerase activity. By contrast, normal human somatic tissues, other than stem cells, do not possess detectable levels of this enzyme. It is an attractive hypothesis that both immortalization and carcinogenesis are associated with telomerase expression. During normal cell differentiation in, these telomeres shorten. However, the telomeres are renewed by the effect of the enzyme telomerase in cancer cells and stem cells. Telomerase activity normally decreases during cell differentiation. Since the cell loses its capacity for proliferation, fully differentiated cells enter a resting state and consequently die. However, telomerase retains its efficacy in several cancer types, or it is reactivated. Therefore, the telomere length remains constant in these cells and they proliferate indefinitely (they become immortal). 3. Genetic instability: This situation is caused by defects in the DNA repair process and in DNA mismatch recognition, which results in the heterogeneity of cancer cells. Cancer cells form clones that gradually respond less and less to the proliferation control mechanism. The ability of these clones to survive in foreign environments also gradually increases and they gain the ability to metastasize. 4. Loss of contact inhibition: Normal cells growing in culture medium cannot divide if they do not stick to the bottom layer. Normal cells also lose their ability to divide when they form a layer across the whole surface. They do not divide, 3 even in the presence of all of the required growth factors and other nutritional elements in the Petri dish. Cancer cells, however, divide independently without needing to stick to the bottom layer of the Petri dish. Furthermore, they continue to grow even when they have formed more than one layer in the cell culture. 5. Continuous increase in proliferation: This situation is a characteristic of cancer cells in culture medium. Although cancer cells consume the required nutrition factors, they continue to grow, and they actually end up killing themselves. 6. Metastasis: This feature is not found in benign tumors and normal cells. Metastasis occurs because of the loss of cellular proteins responsible for adherence to the extracellular matrix, intercellular interaction defects, abnormalities in cell adherence to the basal membrane, abnormalities in basal membrane production, or the destruction of basal membrane by enzymes like metalloproteases. 2.2.Cell cycle checkpoints: Normal cells have mechanisms for detecting errors in the DNA sequence. A group of repair mechanisms replace damaged nucleotides with normal molecules when the DNA is damaged. These mechanisms ensure that the genetic material in each of the two daughter cells is the same as that of the mother cell. 4 A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable (figure 2.1). -First checkpoint of the cell cycle: This is located in the late G1 phase just prior to the S phase. DNA should be error-free before it exits from G1, and even extracellular signals specific for DNA synthesis and all of the mechanisms should work properly. If any damage is detected, the cell will not be allowed to continue to the S phase of interphase, and try to either repair the damage or die by apoptosis. -Second checkpoint of the cell cycle: This is located in the late G2phase just prior to the M phase.G2checkpoint ensures all of the chromosomes have been replicated and that the replicated DNA is not damaged before cell enters mitosis.Cell cycle inhibitors stop the cell cycle until they are sure that the new daughter cells will have perfect genetic copies of the DNA in the original cell. If DNA replication does not finish entirely and correctly, or not all of the proteins, spindle cells and other materials needed for mitosis are formed completely, the cell cycle stops at this checkpoint until all errors have been corrected. It then enters the M phase. - Third checkpoint of the cell cycle: This is located in the late M phase. M checkpoint determines whether all the sister chromatids are correctly attached to the spindle microtubules before the cell enters the irreversible anaphase stage. 5 Figure 2.1:Cell cycle checkpoints 6