Module 5: Regulation of Cell Cycle and Cancer PDF
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This document provides lecture notes on the regulation of the cell cycle and cancer, including the various phases of the cell cycle and the role of cyclins and cyclin-dependent kinases (CDKs) in controlling cell cycle progression. It also discusses checkpoints crucial for ensuring accurate cell division and the potential implications of dysregulation in cell cycle control on cancer development.
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Lecture Notes in BIO 1 – Cell and Molecular Biology MODULE 5:REGULATION OF CELL CYCLE AND CANCER 1. Cell Cycle Regulation a. Cell Checkpoints The cell cycle is the of steps that cells take to grow, develop, and reproduce. It can be...
Lecture Notes in BIO 1 – Cell and Molecular Biology MODULE 5:REGULATION OF CELL CYCLE AND CANCER 1. Cell Cycle Regulation a. Cell Checkpoints The cell cycle is the of steps that cells take to grow, develop, and reproduce. It can be broken down into five steps: 1. G1 Phase - During the G1 Phase, the cell grows and stores up energy that it will use during cell division. Nutrients are taken in and all the usual cell processes take place. Once cells are fully grown, they proceed on to the S Phase. 2. S Phase - During the S Phase, the DNA in the cell's nucleus is copied. This means that the cell then attains two copies of all the necessary DNA for normal cell activity, leaving a full set to be transferred into the new cell that will be created after the cell divides. 3. G2 Phase - During this phase, the cell prepares for cell division. This phase represents a time gap between the time when the cell copies its DNA and when it divades. 4. M Phase - During this phase, cell division takes place through Mitosis. 5. Cytokinesis - During Cytokinesis, the cytoplasm in the cell divides and the cell's membrane pinches inward and the cell begins to divide. b. Cyclins and Cyclin-Dependent kinases ( CDK’S) - Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. ROLE OF CYCLINS IN CELL CYCLE PROGRESSION Cyclins are crucial regulatory proteins that control the progression of the cell cycle. They do this by forming complexes with cyclin-dependent kinases (CDKs), which are enzymes that drive the cell cycle forward. Here's a closer look at how cyclins influence cell cycle progression: 1. Cyclin-CDK Complexes Cyclins activate CDKs by binding to them, which is necessary for CDK activity. CDKs are only active when bound to a cyclin, and the cyclin-CDK complexes phosphorylate target proteins that are involved in various cell cycle transitions. Each cyclin-CDK complex is specific to a particular phase of the cell cycle. 2. Cyclin Types and Their Roles Cyclin D: This cyclin is associated with the G1 phase of the cell cycle. Cyclin E: Cyclin E forms a complex with CDK2 and is crucial for the transition from the G1 phase to the S phase. Cyclin A: Cyclin A binds to CDK2 and CDK1. In the S phase, cyclin A-CDK2 complexes are involved in DNA replication and ensuring that the DNA is properly duplicated. Cyclin B: Cyclin B associates with CDK1 (also known as CDC2) and is essential for the G2 to M phase transition. 3.. Regulation and Degradation - Cyclin levels fluctuate during the cell cycle. 4. Checkpoint Controls - Cyclins and CDKs are also involved in cell cycle checkpoints - mechanisms that ensure the cell cycle does not proceed if there are issues such as DNA damage or incomplete DNA replication. 5. Implications in Disease - Dysregulation of cyclins and CDKs can lead to uncontrolled cell division and contribute to cancer development. ACTIVATION OF CDK’S AND THEIR INVOLVEMENT IN CONTROLLING THE CELL CYCLE Activation Mechanism: Cyclin Binding: CDKs are activated through their binding with specific cyclins. Phosphorylation: Full activation of cyclin-CDK complexes often requires additional phosphorylation. Controlling the Cell Cycle: G1 Phase: Cyclin D-CDK4/6 complexes partially phosphorylate the retinoblastoma (Rb) tumor suppressor protein. G1 to S Transition: Cyclin E-CDK2 complexes fully phosphorylate Rb, further driving the cell into the S phase. S Phase: Cyclin A-CDK2 complexes are crucial for the progression through S phase by regulating DNA replication. G2 Phase and M Phase: Cyclin A-CDK1 complexes aid in the transition to M phase. Checkpoints: CDKs and cyclins are regulated by checkpoints in the cell cycle (end of G1, end of G2, and during metaphase) to ensure accurate cell division. C. TUMOR SUPPRESSOR GENES AND ONCOGENES - Our bodies are made up of trillions of cells, which must work together to keep us healthy. The role of tumor suppressor genes in cell cycle (progression) regulation and preventing cancer. - Cell growth is normally controlled by the actions of certain genes inside each cell. Cancer begins when cells in the body become abnormal and start to grow out of control. This happens where there are changes in genes that affect cell growth. The main types of genes that play a role in cancer are: Oncogenes Tumor suppressor genes DNA repair genes 2. Cell Cycle Dysregulation in Cancer A cell cycle is a series of events that takes place in a cell as it grows and divides. A cell spends most of its time in what is called interphase, and during this time it grows, replicates its chromosomes, and prepares for cell division. The cell then leaves interphase, undergoes mitosis, and completes its division. The resulting cells, known as daughter cells, each enter their own interphase and begin a new round of the cell cycle. A regulatory mechanism - is the combination of steps or processes that an organism can engage to ensure that a biological process is controlled. Most regulatory mechanisms are performed to help maintain homeostasis. What is Cell Division? - Cell division happens when a parent cell divides into two or more cells called daughter cells. Cell division usually occurs as part of a larger cell cycle. 2 types of cell division 1. Meiosis is a type of cell division that reduces the number of chromosomes in the parent cell by half and produces four gamete cells. This process is required to produce egg and sperm cells for sexual reproduction. 2. Mitosis, a process of cell duplication, or reproduction, during which one cell gives rise to two genetically identical daughter cells. WHAT HAPPENS WHEN CELL DIVISION GOES WRONG? - When the cell cycle proceeds without control, cells can divide without order and accumulate genetic errors that can lead to a cancerous tumor. - Cancer cells are different from normal cells because they divide out of control are immature and don’t develop into mature cells with specific jobs avoid the immune system ignore signals that tell them to stop dividing or to die when they should don’t stick together very well and can spread to other parts of the body through the blood or lymphatic system grow into and damage tissues and organs. As cancer cells divide, a tumour will develop and grow. Cancer cells have the same needs as normal cells. They need a blood supply to bring oxygen and nutrients to grow and survive. When a tumor is very small, it can easily grow, and it gets oxygen and nutrients from nearby blood vessels. Cyclins - regulate the activity of their CDK partners and also modulate their substrate specificity. Cyclin-dependent kinases (CDKs)-- Of the many proteins involved in cell cycle control, cyclin-dependent kinases (CDKs) are among the most important. CDKs are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression. Cell cycle checkpoints – are control mechanisms involving different groups of molecules that act at critical stages of the cell cycle, i.e., the G1, G1/S, S and G2 or G2/M stages, and, by integrating signals coming from both inside and outside the cells, allow the transition to the next phase of the cell cycle Dysregulation in cancer – dysregulated metabolism gives cancer cells the ability to acquire the nutrients it needs from a nutrient-poor environment to both survive as well as build new biomass. Mutation in CDKs– Mutations of CDKs are rare, gene amplification or protein overexpression of the cyclin partners such as cyclin D1 is frequently encountered in various malignancies, including lung cancer. Tumor Suppressor – Tumor suppressor genes are normal genes that slow down cell division or tell cells to die at the right time (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer. What happens when a tumor suppressor is mutated? - When a tumor suppressor gene is inactivated by a mutation, the protein it encodes is not produced or does not function properly, and as a result, uncontrolled cell division may occur. Such mutations may contribute to the development of a cancer. P53 – inhibits glucose uptake and glycolysis by suppressing the expression and translocation of glucose transporter proteins such as GLUT1 and GLUT4 The retinoblastoma protein (RB) regulates the G1-S check point in the cell cycle and activity of transcription factors. In conjunction with cyclin dependent kinases and inhibitors of cyclin dependent kinases, RB regulation of the cell cycle is bypassed in cancers. The activation of oncogenes involves genetic changes to cellular protooncogenes. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasms: (1) mutation, (2) gene amplification, and (3) chromosome rearrangements. What are the consequences of uncontrolled cell division? - Disruption of normal regulation of the cell cycle can lead to diseases such as cancer. When the cell cycle proceeds without control, cells can divide without order and accumulate genetic errors that can lead to a cancerous tumor. WHAT IS THE CONSEQUENCES OF DYSREGULATION IN GENOMIC INSTABILITY? - A direct consequence of genomic instability is cell cycle stress, changes in gene expression and changes in gene regulation. Ultimately, this could explain age-related cellular degeneration and functional decay. The ultimate outcome of genomic instability is aging, cancer and degenerative disease. Death Cells - They evade apoptosis, the mechanism that programs cell death once cells become damaged. Normally, apoptosis helps keep an organism healthy through growth and development, maintaining body tissue by removing infected or damaged cells. 3. Causes and Risk Factors A. Environmental Factors: - Discuss environmental factors that can increase the risk of cancer (e.g., radiation, chemicals, viruses). Radiation - Ultraviolet (UV) Radiation: Prolonged exposure to UV radiation from the sun or tanning beds can lead to skin cancers, including melanoma, basal cell carcinoma, and squamous cell carcinoma. UV rays damage the DNA in skin cells, leading to mutations. - Ionizing Radiation: Exposure to high levels of ionizing radiation, such as X-rays, gamma rays, and radon gas, can increase the risk of cancers like leukemia, breast cancer, and lung cancer. For example, individuals exposed to nuclear radiation or radiation therapy for other conditions have an elevated risk of developing cancer. Chemicals and Carcinogens: Tobacco Smoke: Cigarettes contain numerous carcinogenic chemicals, such as benzene, formaldehyde, and arsenic. Smoking is strongly associated with lung cancer and other cancers, including throat, bladder, and pancreatic cancer. Asbestos: Asbestos, commonly used in construction materials, has been linked to mesothelioma, a type of cancer affecting the lining of the lungs and abdomen. Benzene: Exposure to benzene, a chemical used in industrial processes, can lead to an increased risk of leukemia and other blood-related cancers. Pesticides and Industrial Chemicals: Prolonged exposure to certain pesticides, herbicides, and industrial solvents is associated with a higher risk of cancers, including non-Hodgkin lymphoma and prostate cancer. Viruses and Bacteria: Human Papillomavirus (HPV): HPV, a sexually transmitted virus, is one of the primary causes of cervical cancer and is also associated with throat and anal cancers. Hepatitis B and C: These viruses can lead to chronic liver infections, which significantly increase the risk of liver cancer (hepatocellular carcinoma). B. Lifestyle Factors: How lifestyle choices, such as smoking, diet, and physical activities can impact cancer risk. - Lifestyle risk factors play a significant role in determining the likelihood of developing cancer. The choices we make in our daily lives, such as smoking, diet, and physical activities. Tobacco: Smoking is the leading cause of preventable death and is linked to numerous cancers, including lung, throat, mouth, and esophagus cancers. Second-hand smoke is also a serious risk factor, contributing to thousands of deaths annually. Diet: A diet high in red and processed meats, as well as unhealthy fats, can raise the chances of developing cancers such as pancreatic, bowel, and breast cancers. Poor dietary choices reduce the body's ability to function optimally and resist disease. There are various physical activities you can engage in to reduce cancer risk and improve overall health. These activities can be categorized into aerobic, strength training, flexibility exercises, and balance activities: Aerobic Activities: These are great for cardiovascular health and help reduce body fat. 1. Walking briskly 5. Dancing 2. Running or jogging 6. Hiking 3. Swimming 7. Rowing 4. Cycling Strength Training: These exercises build muscle and improve metabolism. 1. Lifting weights 4. Pilates 2. Using resistance bands 3. Bodyweight exercises (push-ups, squats, lunges) Flexibility Exercises: These improve joint health and prevent injury. 1. Stretching 2. Yoga 3. Tai Chi Balance Activities: Important for coordination and reducing falls, especially for older adults. 1. Standing on one leg 2. Heel-to-toe walking 3. Balance-focused yoga poses (tree pose) – Incorporating a mix of these activities into your routine can provide a comprehensive approach to fitness and cancer prevention. Aim for at least 150 minutes of moderate-intensity aerobic activity per week, along with strength training on two or more days. 4. DIAGNOSIS AND TREATMENT A. Cancer Diagnosis (methods for detecting cancer e.g., imaging, biopsies, blood test). Staging and grading of cancer. How Is Cancer Diagnosed? - There is no single test that can accurately diagnose cancer. The complete evaluation of a patient usually requires a thorough history and physical examination along with diagnostic testing. Many tests are needed to determine whether a person has cancer, or if another condition (such as an infection) is mimicking the symptoms of cancer. Cancer diagnosis methods: Lab tests Diagnostic imaging Endoscopic exams Genetic tests Tumor biopsies What are the different types of lab tests used to diagnose cancer? - Clinical chemistry uses chemical processes to measure levels of chemical components in body fluids and tissues. The most common specimens used in clinical chemistry are blood and urine. The following are some of the more common laboratory tests: Blood tests Complete blood count (CBC) Urinalysis Tumor markers Diagnostic imaging - Diagnostic radiology has greatly advanced in recent years with the development of new instruments and techniques that can better detect cancer and also help patients avoid surgery. The diagnostic radiology staff and physicians at the Stanford Cancer Center are leaders in their field and have access to the most advanced technology available today for imaging of cancer. What are the different types of diagnostic imaging? - Imaging is the process of producing valuable pictures of body structures and organs. It is used to detect tumors and other abnormalities, to determine the extent of disease, and to evaluate the effectiveness of treatment. There are three types of imaging used for diagnosing cancer: Transmission imaging Reflection imaging Emission imaging What are the different types of endoscopic examinations used to diagnose cancer? Types of endoscopies include: Cystoscopy (also called cystourethroscopy) Colonoscopy Endoscopic retrograde cholangiopancreatography (ERCP) Esophagogastroduodenoscopy (also called EGD or upper endoscopy) Sigmoidoscopy What are the different types of tumor biopsies used to diagnose cancer? - A biopsy is a procedure performed to remove tissue or cells from the body for examination under a microscope. Some biopsies can be performed in a physician's office, while others need to be done in a hospital setting. The following are the most common types of biopsies: Endoscopic biopsy Bone marrow biopsy Excisional or incisional biopsy Fine needle aspiration biopsy Punch biopsy Shave biopsy Skin biopsy 5. Prevention and Early Detection: a. Cancer Prevention: Human papillomavirus (HPV) vaccine The HPV vaccine protects against the types of HPV that most often cause cervical, vaginal, and vulvar cancers. Things that you need to do: HPV vaccination is recommended for preteens aged 11 to 12 years, but can be given starting at age 9. HPV vaccination also is recommended for everyone through age 26 years, if they are not vaccinated already. HPV vaccination is not recommended for everyone older than age 26 years. However, some adults age 27 through 45 years who are not already vaccinated may decide to get the HPV vaccine after speaking with their doctor about their risk for new HPV infections and the possible benefits of vaccination. HPV vaccination in this age range provides less benefit, as more people have already been exposed to HPV. * If you get the HPV vaccine before age 15, you only need two doses, 6 to 12 months apart. If you start after turning 15, you’ll need three doses. * The HPV vaccine prevents new infections but doesn’t treat existing ones. That’s why it’s most effective when given before any exposure to the virus. Even if you’ve had the vaccine, you should still get regular cervical cancer screenings. Facts about HPV HPV is a common virus that can cause 6 types of cancer. Prevention Matters! HPV cannot be treated, but there is a vaccine that can prevent it. The HPV vaccine works best when given between ages 9 and 12, for boys and girls. The HPV vaccine is safe, effective, and long-lasting. Lifestyle Changes: Making healthy choices can lower your cancer risk. This includes not smoking, eating a balanced diet, staying physically active, and avoiding excessive alcohol. Screening Programs: Regular screenings, like mammograms for breast cancer or colonoscopies for colon cancer, can detect cancer early when it’s most treatable. Even if you’re vaccinated, screenings are important for catching cancer early b. Early Detection Importance of early detection Early diagnosis of cancer focuses on detecting symptomatic patients as early as possible so they have the best chance for successful treatment. When cancer care is delayed or inaccessible there is a lower chance of survival, greater problems associated with treatment and higher costs of care. Early diagnosis improves cancer outcomes by providing care at the earliest possible stage and is therefore an important public health strategy in all settings. The role of screening test Mammogram A mammogram is an X-ray examination of the breast. It is used to detect and diagnose breast disease in women who either have breast problems, such as a lump, pain, or nipple discharge, as well as for women who have no breast complaints. The procedure allows detection of breast cancers , benign tumors, and cysts before they can be detected by palpation (touch). Colonoscopies Screening colonoscopy is important to detect and treat early colorectal cancers. It is used to help direct steps in oncologic treatment, including planning for surgical interventions. This activity will discuss and describe the utility of colonoscopy, indications, contraindications, personnel, preparations, and techniques for the procedure. 6. Personalized Medicine Personalized Medicine- is an emerging practice of medicine that uses an individual’s genetic profile made in regard to prevention, diagnosis, and treatment of disease. Benefits of Personalized Medicine - The benefits of personalized medicine are many, ranging from improving diagnostic accuracy to identifying the best treatment option for a patient based on their characteristics. Genomic Profiling (Genomic Characterization) - A laboratory method that uses a sample of tissue, blood, or other body fluid to learn about all the genes interact with each other and with the environment. The general defining feature of cancer is accumulated cell mutation, which manifests as tumors with uncontrolled growth. Despite this complexity and variability, most types of cancer are treated with the same generac therapies. 4 TYPES OF CANCER TREATMENT ❖ Surgery- To remove the cancer or as much of the cancer as possible. ❖ Radiation Therapy- Treats cancer with powerful energy beams. ❖ Chemotherapy- Treats cancer with strong medicines. Most of chemotherapy medicines are giving through a vein. ❖ Immunotherapy- Type of cancer treatment that helps your Immune system fight cancer. 7. ETHICAL AND SOCIAL CONSIDERATIONS Ethical Issues in Cancer Research and Treatment 1. Resource Allocation: Competing Priorities- Limited resources necessitate choices between funding cancer initiatives (screening and tobacco cessation) and addressing urgent health issues like infant mortality, maternal health, and road safety. Equity vs. Efficiency: The challenge lies in balancing cancer prevention efforts with immediate health crises, raising questions about equitable healthcare access and the efficient use of resources. 2. Public Support and Perception: Taxpayer Sentiment- The extent to which citizens support funding for cancer initiatives over other pressing health concerns reflects societal values, leading to ethical dilemmas regarding which health needs are prioritized. Awareness and Education- The effectiveness of public health campaigns in promoting cancer prevention versus other health issues can significantly influence funding decisions. 3. Long-term vs. Short-term Outcomes: Preventive vs. Reactive Care- While investing in cancer screening and tobacco cessation may provide long-term benefits, immediate health needs (such as reducing infant mortality) may take precedence, raising ethical questions about intervention timing. Impact on Vulnerable Populations- Funding decisions may disproportionately affect vulnerable groups, raising concerns about justice and fairness in healthcare access. 4. Research Funding: Prioritization of Research- Ethical dilemmas arise in determining which health issues receive research funding, especially when cancer research competes with urgent public health crises. Potential for Neglect- Focusing on cancer may lead to the neglect of other critical health areas, raising ethical questions about the comprehensiveness of health planning. 5. Health Outcomes and Quality of Life: Balancing Health Outcomes- Ethical considerations include how to measure and prioritize health outcomes, including quality of life, when making funding allocation decisions. Long-term Health Implications- The potential long-term benefits of cancer prevention must be weighed against the immediate health needs of the population (Ghose et al., 2019). 8. Current Research and Future Directions Current Research and Future Directions in Cancer Biology and Therapy 1. Immunotherapy Advances: Checkpoint Inhibitors: Continued development of drugs that enhance the immune system's ability to recognize and attack cancer cells, showing promise in various cancer types. CAR T-cell Therapy: Innovations in chimeric antigen receptor (CAR) T-cell therapy are expanding its application beyond hematological cancers to solid tumors. 2. Targeted Therapies: Precision Medicine: Advances in genomic profiling allow for more personalized treatment plans based on individual tumor mutations, improving treatment efficacy. Novel Target Identification: Ongoing research is identifying new molecular targets for drug development, particularly in resistant cancer types. 3. Combination Therapies: Synergistic Approaches: Research is focusing on combining different therapeutic modalities (e.g., immunotherapy with chemotherapy or radiation) to enhance overall treatment effectiveness and overcome resistance. 4. Early Detection and Screening: Liquid Biopsies: Development of non-invasive blood tests for early cancer detection and monitoring treatment response, improving patient outcomes through timely intervention. Advanced Imaging Techniques: Innovations in imaging technologies are enhancing the ability to detect tumors at earlier stages. 5. Microbiome Research: Gut Microbiome Influence: Studies are exploring the role of the microbiome in cancer development and treatment response, potentially leading to novel therapeutic strategies. 6. Cancer Prevention Strategies: Lifestyle Interventions: Research is increasingly focusing on the impact of diet, exercise, and lifestyle changes on cancer prevention and recurrence. Vaccination: Continued development of vaccines, such as those targeting HPV and hepatitis B, to prevent virus-related cancers. 7. Artificial Intelligence and Machine Learning: Data Analysis: Utilization of AI and machine learning to analyze large datasets for better understanding cancer biology, predicting treatment responses, and personalizing therapies. 8. Patient-Centric Approaches: Quality of Life Research: Emphasis on integrating patient-reported outcomes and quality of life measures into cancer research and treatment planning (Dede et al., 2023). References: Jurdana, M. (2021). Physical activity and cancer risk. Actual knowledge and possible biological mechanisms. Radiology and Oncology, 55(1), 7–17. https://doi.org/10.2478/raon-2020-0063 Reducing risk for cervical cancer. (2023, October 26). Cervical Cancer. https://www.cdc.gov/cervical-cancer/prevention/index.html?fbclid=IwY2xjawFHjtxleHRuA2FlbQIx MAABHbBEdmDC71LFrC8E2jgj2b01E40gq-ZbIgPUvGpAwjgGl952oxwD2KPp5w_aem_xkecHY5 NWC9__cnLnMRp_g HPV Vaccination and Cancer Prevention | ACS. (n.d.). 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The Scientist Magazine®.https://www.the-scientist.com/precision-medicine-a-new-era-in-cancer-therapy-71556 ?fbclid=IwY2xjawFHlLhleHRuA2FlbQIxMAABHSHPQGEURz4quGdbVjz-7pO2hd9VFDkU_N94O pA3Hxd-YdIwhL-tPgqysg_aem_lrkygf0DYEZq8SvuAAUeSw#:~:text=Precision%20medicine%20f or%20cancer%20treatment,their%20tumor%20and%20its%20microenvironment Prepared by: Besinga, Caila Mae L. Lopena, Jane Kristine B. Salarda, Monaliza P. BSEd – Science 2 Student