Introduction According to the Centre for Health Protection of the Department of Health (2011), cervical cancer becomes the tenth commonest cancer in Hong Kong in 2008. Cervical cancer usually arises from sexual activity and human papillomavirus (HPV) (Bellentir, 2002). In this essay, Human papillomavirus would be further discussed. For example, the signal transport pathway of HPV 16 and HPV 18, which many scientists believe that they are closely related of causing cervical cancer, as well as the HPV vaccine and chemotherapy of cervical cancer, would be discussed.
HPV as the Main Cause of Cervical Cancer Cervical cancer usually starts from the invasion of HPV to the epidermal stratified squamous epithelium of cervix surface (N. D. , 2011). HPV embeds with L1 protein. When virus enters the cell, the L1 protein layer degrades and releases the viral DNA in the nucleus of the host cell. And then the viral DNA transcribes to form mRNA, and attaches on the cellular DNA. Thus, the cellular DNA integrates. Finally it continues the translation process and produces E6 and E7 protein.
HPV consists of 8 genes, oncogene E6 and E7 genes are closely related to the control of transcription process at human as well as the cell cycle. Once HPV enters the cervix cell, it triggers the HPV to have the transcription for production of viral E6 and E7 mRNA and the translation for production of E6 and E7 protein from double strand of the viral DNA. (Lin & Wu, 1990) How E7 Protein Affects the Cell Cycle In the normal cell cycle, after forming the G1Cdk-cyclin complex and inputting of ATP, Rb protein converts from active form to inactive one by phosphorylation (adding of phosphate group).
After that, E2F transcription factor releases and triggers the gene transcription, and then mRNA translates for preparing essential materials like enzymes and protein for DNA synthesis phase (S phase). But when E7 enters the cell, it will bind with Rb protein, keep Rb protein phosphorylated, and destroy the restriction point function. The cell cannot detect whether the cell contains enough materials for carrying the following DNA synthesis phase or not. So that the E2F keeps releasing, and it is not ‘covered’ by Rb protein anymore. The cell cycle does not stop and keeps producing DNA.
This uncontrollable proliferating of cell may finally turns into malignant cell (Nevins, 2001). Also, the p16 protein is also responsible for the D cyclin-Cdk4 activity. When there is few amount of p16, the D cyclin-Cdk4 complex would be more active, Rb protein would also phosphorylate and E2F would accumulate inside the cell. Therefore, p16 protein performs the similar function to E7 protein. (Nevins, 2001) How E6 Protein Affects the Cell Cycle For the normal cell cycle process, when DNA damages, tumor suppressor gene P53 would stop cell division and try to repair the DNA.
If DNA cannot be repaired, P53 would give signal to that particular cell to death. This process calls apoptosis (? ). But if E6 is presence, it would attach the ubiquitin part of P53 protein and destroy the P53. The ubiquitin is used for marking the targeted protein for the further degradation by proteasomes. Hence, if ubiquitin is blocked, no cell can be marked. And the ubiquitin cannot carry further degradation. P53 would not be able to carry out apoptosis anymore. It leads a net increase of existing cells. It results the imbalance of existing cell and dead cells.
The total number of cells would increase. (Hardin, Bertoni & Kleinsmith (2011) How the Secretion of Growth Factors Triggers Tumor Development Once the cell starts abnormally migration, all space would be occupied easily, which would disrupt the growth of the cancer cell. For further enlarging itself, the cancer cell usually secretes some growth factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to trigger the formation of blood vessel (angiogenesis), so that the cancer cell can obtain nutrients for growth.
Angiogenesis depends on various positive (e. g. PD-ECGF, VEGF) and negative (e. g thrombospondin-1, platelet factor-4) regulatory molecules (Wei, Kuo, Chen, Chou, Lai, Lee & Hsieh, 2003). IL-6 Induce Angiogenesis and Tumor Growth In the cervical cancer cell, VEGF and interleukin-6(IL-6) are commonly found. IL-6 is used to stimulate the immune response at first. But some research reveals that IL-6 accelerates the tumor growth and formation of micro vascular network of red blood cell. IL-6 is a kind of pro-inflammatory cytokine which secreted by T-cells and macrophages.
IL-6 would activate VEGF-dependent angiogenesis process, thus blood vessel can be easily formed the cancer cell and enter circulatory system through lymph node or capillary. It promotes the development of cervical tumor through paracrine system or autocrine system. (Wei, Kuo & Chen et al. ) MMP-2 Activity of Degrading Collagen According to Hardin, Bertoni and Kleinsmith (2011), when the growth factor binds to receptor protein which located on cell surface, it triggers the complex signal pathway, causes the division of endothelial cell and secretion of matrix metalloproteinase (MMPs).
In the cervical cancer cell, MMP-2 and MMP-9 play the important roles on tumor invasion and metastasis. MMP-2 acts as a proteinase for degradation of collagen. Collagen is the main component of basal membrane and extracellular matrix, which supporting cells structure from outside. For inhibiting the MMP-2 activity, tissue inhibitors of metalloproteinase (TIMPs) are used. TIMPs would form non-covalent complex with MMP-2 to inhibit MMP-2 activity. Therefore less amount of collagen would be degraded by the MMP-2.
The extracellular matrix can still occupy the intercellular space between cells; and can provide less space for migration of the cancer cells. Thus the proliferation of cancer cell can be suppressed. The metastasis process slows down. (Roomi, Monterrey, Kalinovsky, Rath & Niedzwiecki, 2010) HPV Vaccine Mechanism Since cervical cancer mainly develops from high-risk HPV, by injecting weaken HPV 16 and HPV 18, the opportunity of suffering cervical cancer and genital warts can be greatly reduced. The HPV usually consists of recombinant virus-like particle of HPV type 1, 11, 16 and 18.
(Type 1 and 11 are for genital warts, while type 16 and 18 are for cervical cancer). These particles contain only the viral surface but lack of DNA component. Since every HPV has its unique protein coat envelope, and the immune response initiates by detecting foreign cell surface. The viral DNA is not needed in HPV vaccine. It can avoid the risk that integrated, mutated DNA formed after vaccination. When these viruses-like particles enter our body, it would attach to the cells and trigger a chain reaction to produce the virus-neutralizing antibody. (National Cancer Institute, 2011).
The Reason Why HPV Do Not Trigger Immune Response However, foreign HPV is completely different from the HPV which is pre-existing in our body. It is interesting that the pre-existing HPV in body would not cause any immune response. It is because the host cell exposes low level of viral protein, and there is no inflammation in the nearby region of the cancer cell. Immune response may not be easily triggered if no induction of inflammation occurs. Thus the HPV activity is down regulated. Even high-risk HPV E6 and E7 protein content increase, it would not trigger the cell-mediated immune system.
As a result, the invasive process of HPV can further carry out without any obstacles. (Stanley, 2005) Treatment of Cervical Cancer – Chemotherapy Besides vaccination, chemotherapy would also be used to treat people who suffer from cervical cancer. Topotecan is a chemotherapy drug that would use for treating cervical cancer. Topotecan can block the enzyme topoisomerase-1 activity. This enzyme is used for adjusting the steady-state level of DNA at different stages like transcription to form viral mRNA, translation of protein production, interaction in protein and repair of the viral DNA cells during cell division.
And topoisomerase-1 leads the further growth of tumor and it becomes bigger in size. Blocking of the topoisomerase-1 can prevent the repairing of damaged viral DNA and the cancer cell would eventually die. Therefore the tumor growth can be repressed. (CancerHelp UK. , 2010) Treatment of Cervical Cancer – Radiation Therapy Radiation therapy is also used to cure the cervical cancer by using high-energy rays like X-ray to kill cancer cells and shrink tumor cells. There are two types of radiation therapy, which are external and internal.
By emitting the high-energy light to tumor region, the strong ionizing effect would remove electron from the molecules, in order to break the double strand DNA, or even mutate just like the deletion of organic base. It alters the protein conformation and causes malfunction of some cancer cells. (Bellentir, 2002) Development of Therapeutic HPV Vaccine Nowadays, the scientists want to pay attention to develop the therapeutic HPV vaccine. It focuses on the oncogenes of cervical cancer, E6 and E7. E6 and E7 are responsible for the growth of cervical cancer.
If the production of E6 and E7 protein can be restricted, it will not trigger the further carcinoma development. But, there are still some potential hazards exist that cause harm to us. By injecting the therapeutic vaccine to mice, it cannot cure the mice with large premalignant tumors. In order to trigger strong immune response, Th1/CTL which involves strong tumor-specific response is needed. But it is not easy to apply in clinical because it may involve the changing of microenvironment. (Burg & Melief, 2011) Conclusion To conclude, cervical cancer mainly caused by HPV 16 and HPV 18.
Once HPV invades to the cervix cell, it starts to produce E6 and E7 protein, which will affect the normal Rb protein and P53 function. Thus the cell cycle would be disrupted and the cell starts to grow abnormally. When the HPV invades the basement membrane of cervix, it would further proliferate and enlarge its size. The cancer cells are able to secrete MMPs for favoring the production of blood vessel, by migrating and organizing endothelial cell into hollow tubes. After travelling at circulatory system, cancer cells can form metastases at other regions and start another complex cascade of events.
In Hong Kong, Cervical Screening Programme was launched on 2006. It encouraged female to carry out regularly checking on cervical smear, to discover and to cure cervical cancer as soon as possible. (1686 words) References Bellentir, K. (2002), Treatment of cervical cancer, (2nd Edn. ), Cancer sourcebook for women (pp. 79-84). US: Omnigraphics. Burg, S. H van der & Melief, C. JM. (2011). Therapeutic vaccination against human papilloma virus induced malignancies. Current Opinion in Immunology, 23, 1-6. CancerHelp UK. (2010). About chemotherapy for cervical cancer.
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