Cell Signaling and Cancer PDF

Lecture Notes in Bio 1: Cell and Molecular Biology Cell Signaling and Cancer Introduction to Cell Signaling 4. Direct cell-cell signaling: Adjacent cells communicate through gap...

Lecture Notes in Bio 1: Cell and Molecular Biology Cell Signaling and Cancer Introduction to Cell Signaling 4. Direct cell-cell signaling: Adjacent cells communicate through gap junctions or cell surface proteins. Cell signaling is a fundamental process that allows cells to communicate with each other and respond to environmental cues. This communication is essential for the proper functioning of multicellular organisms. In cancer, aberrant cell signaling can lead to uncontrolled cell growth and division. Types of Cell Signaling 1. Endocrine signaling: Hormones travel through the bloodstream to reach distant target cells. In cancer, these signaling mechanisms can be disrupted, leading to abnormal cell behavior. Signal Transduction Pathways Signal transduction pathways- are essential processes that allow cells to communicate and respond to external signal. 2. Paracrine signaling: Signaling molecules act on nearby cells They involve three main stages: 1. Reception: A signaling molecule (ligand) binds to a receptor on the cell surface. 2. Transduction: The binding activates a series of proteins inside the cell, often through a cascade of biochemical reactions, amplifying the signal. 3. Response: The cell executes a specific action, such as changing gene expression, altering metabolism, initiating cell division. 3. Autocrine signaling: Cells respond to signals they produce themselves. Molecular Components of Cell Signaling Receptors A. Receptors- are specialized proteins or molecular structures that detect and respond to specific signals, such as hormones, neurotransmitters, or environmental stimuli. They are essential for communication between cells and their environment, playing a key role in maintaining cellular and physiological functions. Types of Cell Surface Protein phosphorylation is a critical regulatory mechanism in cellular signaling pathways. It involves the addition of a phosphate group -Plasma Membrane (PO₄³⁻) to specific amino acids (typically serine, threonine, or tyrosine) - Cycocalyx in a protein, catalyzed by protein kinases. This modification alters the - Cilia and Flagella protein's function, activity, stability, or location, thereby influencing - Microvilli various cellular processes such as metabolism, cell division, and gene - Cell Wall expression. Intracellular receptors: These are typically found in the cytoplasm or Key Regulatory Mechanism in Signaling Pathways nucleus and include steroid hormone Phosphorylation is a biochemical process where a phosphate group is added to a protein. receptors. 1. Activation or Inhibition of Proteins: Phosphorylation often acts as an "on" or "off" switch for proteins. For example, the Ligand-receptor interactions: initiate signaling cascades that phosphorylation of enzymes can activate or inhibit their catalytic ultimately lead to changes in cell behavior. In cancer, mutations in activity. In some cases, phosphorylation induces conformational receptors or alterations in their expression levels can contribute to changes that make the protein functionally active (e.g., activation of uncontrolled cell growth. glycogen phosphorylase in response to adrenaline). B. Second Messengers 2. Signal Amplification: Protein phosphorylation is a key mechanism Play a crucial role in amplifying and relaying signals from extracellular in the amplification of signaling cascades. A single activated receptor stimuli (often called "first messengers") to target molecules inside the can trigger the activation of many downstream kinases, which cell. These intracellular signaling molecules help coordinate a wide phosphorylate numerous target proteins, leading to a large-scale variety of cellular responses, including changes in metabolism, gene cellular response. This is seen in pathways like the MAPK (mitogen- expression, growth, and differentiation. activated protein kinase) cascade. Role of Second Messengers 3. Cell Cycle Control: In cell division, phosphorylation regulates the activity of key cyclins and cyclin-dependent kinases (CDKs). 1. Amplification of the Signal: Second messengers amplify the initial Phosphorylation ensures proper timing of processes like DNA signal received by the receptor. A single molecule of the first replication, mitosis, and cytokinesis. For example, the retinoblastoma messenger (such as a hormone or neurotransmitter) can trigger the protein (Rb) is phosphorylated during the cell cycle to control production of many second messenger molecules, leading to a progression from the G1 to S phase. cascade of intracellular events. 4. Gene Expression Regulation: Phosphorylation of transcription 2. Rapid and Localized Signal Transmission: Second messengers factors influences gene expression. For instance, CREB (cAMP allow for fast, transient responses to external stimuli. They often response element-binding protein) is phosphorylated in response to spread throughout the cytoplasm (or in some cases, into specific signaling by cAMP and promotes the transcription of genes involved organelles like the nucleus or mitochondria), rapidly distributing the in cell survival and memory formation. signal within the cell. This makes it possible to achieve a rapid cellular response, such as enzyme activation or changes in ion concentrations. Major Signaling Pathways 3. Integration of Signals: Second messengers can integrate signals from multiple different pathways and coordinate complex cellular MAPK/ERK Pathway- plays a crucial role in cell proliferation and responses. For example, several different types of second survival. It involves a cascade of protein kinases that transmit signals messengers might converge on the same target molecules, allowing from the cell surface to the nucleus. for coordinated regulation of cellular functions. Role in Cell Proliferation and Survival: 4. Activation of Protein Kinases: Many second messengers activate protein kinases, which are enzymes that phosphorylate other proteins, -The MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular altering their activity. This is one of the most common ways by which signal-Regulated Kinase) pathway- is typically activated by growth second messengers influence cellular processes such as metabolism, factoThe MAPK/ERK pathway consists of a series of protein kinases gene expression, or cell division. that communicate signals from the cell surface to the nucleus. 5. Regulation of Gene Expression: Second messengers can also Dysregulation in Cancer: influence transcription factors that regulate gene expression. For example, some second messengers activate kinases that -In cancer, the MAPK/ERK pathway is often dysregulated. Oncogenic phosphorylate and activate transcription factors, leading to changes in mutations in upstream components of the pathway (such as mutations the synthesis of proteins needed for cellular responses. in Ras, BRAF, or other kinases) can result in continuous activation of the MAPK/ERK pathway. -This persistent activation promotes uncontrolled cell proliferation, survival, and metastasis—hallmarks of cancer. Dysregulation of the C. Protein KInases and Phosphorylation MAPK/ERK pathway is commonly observed in a wide range of cancers, including melanoma, colorectal cancer, and non-small cell lung cancer.  The immune system plays a critical role in protecting the body from Tumor Suppressor Pathways harmful pathogens, such as bacteria, viruses, fungi, and parasites, as well as detecting and eliminating abnormal cells, including cancer cells. Tumor Suppressor Pathways- are cellular mechanisms that regulate cell growth, division, and death. They act as a safeguard against Immune System Recognizes and Target Cancer Cells uncontrolled cell proliferation, which can lead to cancer. These pathways involve a network of genes and proteins that work together -Recognition of Abnormalities in Cancer Cells to maintain cellular homeostasis. -Detection by Immune Cells -Immune Response Activation Tumor Suppressor Role and Regulation: -Immune Evasion by Cancer Cells -Immune Surveillance and Tumor Clearance p53, often referred to as the "guardian of the genome," is a transcription factor that responds to cellular stress, such as DNA damage, oxidative stress, and hypoxia. B. Immunotherapy Upon activation, p53 induces cell cycle arrest, DNA repair, or -It represents a revolutionary approach to cancer treatment that apoptosis, depending on the severity of the stress. leverages the body's own immune system to fight cancer. Unlike traditional therapies like chemotherapy and radiation, which target The activity of p53 is tightly regulated by a complex network of cancer cells directly, immunotherapy aims to enhance or modify the proteins, including MDM2, which binds to p53 and promotes its immune response to specifically target and eliminate tumor cells. degradation. Immune checkpoint inhibitors: are a class of immunotherapy that A. p53 Mutations in Cancer: work by blocking the immune checkpoints—molecules that normally suppress immune responses. Cancer cells often exploit these Mutations in the p53 gene are frequently found in a wide range of checkpoints to escape detection and destruction by the immune human cancers, making it one of the most commonly mutated genes system. By inhibiting these checkpoints, checkpoint inhibitors "release in cancer. the brakes" on the immune system, allowing T cells and other immune cells to more effectively attack cancer cells. These mutations often lead to the loss of p53 function, allowing cells with damaged DNA to proliferate unchecked, contributing to CAR-T cell therapy: This involves genetically modifying a patient's T tumorigenesis. cells to express chimeric antigen receptors (CARs) that target specific cancer antigens. B. RB Pathway: Regulation of the cell cycle by RB The retinoblastoma (RB) protein is a key regulator of the cell cycle, particularly the G1-S phase transition. RB binds to and inhibits transcription factors called E2F proteins, which are essential for cell cycle progression. When RB is phosphorylated by cyclin-dependent kinases (CDKs), it releases E2F, allowing the cell cycle to proceed. Signaling and Metastasis A. Cell Motility and Invasion Dysregulation in Cancer: Cell migration and invasion are key processes that allow tumors to Inactivation of the RB pathway, often through mutations or deletions spread from their original site to other parts of the body, a process in the RB gene or its upstream regulators, is a common event in many known as metastasis. These processes are heavily influenced by a cancers. variety of signaling pathways that regulate cellular behaviors, including motility, adhesion, and the remodeling of the extracellular matrix. Loss of RB function leads to uncontrolled cell proliferation and tumor formation. Below are the main signaling pathways involved in cancer cell migration and invasion: Immune Signaling and Cancer Rho GTPase Signaling- Regulates cell shape, movement, and migration, critical for cancer cell invasion and metastasis. A. Role of the Immune System PI3K/Akt/mTOR Pathway- Controls cell growth, survival, and 2. Compensatory Pathways may be activated, such as MAPK metabolism; often overactive in cancer, driving uncontrolled cell signaling in response to BRAF inhibitors. proliferation and resistance to death. 3. Tumor Microenvironment Changes (e.g., increased angiogenesis) MAPK/ERK Pathway- Regulates cell proliferation and migration; can protect cancer cells from treatment. mutations in components like Ras or BRAF lead to tumor growth and metastasis. Emerging Topics Wnt/β-catenin Signaling- Governs cell fate and proliferation; dysregulated in cancers, driving uncontrolled cell division and metastasis. A.Cancer stem cells TGF-β Signaling- Involved in cell growth and differentiation; in cancer, Role of Cancer stem cells in tumor initiation and progression it can promote metastasis through epithelial-to-mesenchymal transition (EMT). Initiating Tumors: CSCs have the ability to self-renew and differentiate into various tumor cell types, driving the growth and B. Angiogenesis refers to the process through which new blood persistence of the tumor. vessels form from pre-existing vessels. It is a crucial physiological process that supports growth, tissue repair, and wound healing. Contributing to Tumor Heterogeneity: They generate diverse cell Role in Tumor Growth and Metastasis populations within the tumor, which supports its adaptability and aggressiveness. Tumor Growth: By delivering oxygen and nutrients, allowing the tumor to expand. Facilitating Progression: CSCs are resistant to conventional therapies, such as chemotherapy and radiation, due to their ability to Metastasis: By providing pathways (through newly formed, abnormal blood vessels) for tumor cells to enter the bloodstream and spread to repair DNA, evade cell death, and remain dormant. This resistance other parts of the body. allows them to promote tumor growth and metastasis. Driving Recurrence: CSCs can survive treatment and later Therapeutic Targeting of Signaling Pathways regenerate the tumor, leading to relapse. A.Targeted therapies- are a class of cancer treatments that aim to interfere with specific molecules or signaling pathways that are involved in the growth, survival, and spread of cancer cells. Targeted C. Liquid biopsy therapies often focus on key signaling pathways that regulate cellular -It is a minimally invasive diagnostic technique that involves analyzing processes like proliferation, apoptosis, angiogenesis, and metastasis. blood or other bodily fluids to detect cancer-related biomarkers. This method has gained significant attention in cancer detection, monitoring, B.Challenges and resistance and personalized treatment. Unlike traditional tissue biopsies, which require surgical procedures, liquid biopsy allows for continuous, real- CHALLENGES time monitoring of cancer through non-invasive blood-based Tumor Heterogeneity: Cancer cells within the same tumor may have biomarkers. different genetic mutations, making it difficult for targeted therapies to treat all cells effectively. Ethical Considerations Resistance Mechanisms: Cancer cells can develop resistance to targeted therapies through various mechanisms. A. Ethical Issues in Cancer Signaling Research: Off-Target Effects: Targeted therapies can sometimes affect normal cells or proteins, causing side effects like skin rashes, gastrointestinal Ethical dilemmas related to clinical trials, patient consent, and access issues, or cardiotoxicity, which can limit therapy doses. to novel therapies. Limited Biomarker Identification: The dynamic nature of tumors and Clinical trials difficulty in obtaining accurate biomarker tests make it challenging to match patients with the right targeted therapy. Vulnerable Populations: Cancer patients, often facing a life- threatening condition, may be more susceptible to coercion or undue RESISTANCE influence in clinical trials. 1. Mutations in the Target (e.g., EGFR mutations or HER2 amplifications) can render therapies ineffective.  Placebo Controls: The use of placebo controls in cancer trials can Minimal Residual Disease (MRD) Detection: Liquid biopsy is raise ethical concerns, especially when effective treatments are increasingly used to detect MRD in hematologic cancers, providing available. early signs of relapse that are not visible through traditional imaging, thus enabling more proactive interventions. Data Sharing: The sharing of clinical trial data can be challenging Metastasis Monitoring: Liquid biopsy tracks CTCs and exosomes to due to privacy concerns, intellectual property rights, and commercial monitor cancer metastasis, identifying early signs of spread in cancers interests. like prostate and breast cancer. Patient consent Informed Consent: Ensuring that patients fully understand the risks, benefits, and alternatives of participating in clinical trials is crucial. Cultural and Linguistic Barriers: Patients from diverse backgrounds may face challenges in understanding consent information. Decisional Capacity: Patients with advanced cancer may have diminished decisional capacity, requiring careful consideration of their best interests. Access to Novel therapies Equity and Justice: Ensuring equitable access to novel cancer therapies, regardless of socioeconomic status, geographic location, or insurance coverage, is a major ethical challenge. Pricing and Reimbursement: High drug prices can limit access to life-saving treatments. Clinical Trial Participation: Access to clinical trials may be limited, especially for patients in under served areas. Current Research and Future Directions A. Recent Advances Improved Detection Technologies: Advances in digital droplet PCR, next-generation sequencing (NGS), and CRISPR-based diagnostics have enhanced the sensitivity and specificity of liquid biopsy, enabling the detection of low-abundance biomarkers such as ctDNA, CTCs, and exosomes for early cancer detection. Multi-Cancer Early Detection: The development of multi-cancer early detection (MCED) tests, like Galleri, which detects over 50 types of cancers through ctDNA methylation patterns, holds promise for screening large populations and identifying cancers before symptoms appear. Personalized Treatment Monitoring: Liquid biopsy is being used to monitor treatment response and detect resistance mutations in real time, allowing for timely adjustments in therapy. For example, it tracks EGFR mutations in NSCLC and KRAS mutations in colorectal cancer to personalize treatment. References Pang, K., Wang, W., Qin, J., Shi, Z., Hao, L., Ma, Y., Xu, H., Wu, Z., Pan, D., Chen, Z., & Han, C. (2022). Role of protein phosphorylation in cell signaling, disease, and the intervention Professional, C. C. M. (2024, May 1). Angiogenesis. therapy. MedComm, 3(4). https://doi.org/10.1002/mco2.175 Cleveland Clinic. https://my.clevelandclinic.org/health/articles/24206- Mian, S. A., Anjos-Afonso, F., & Bonnet, D. (2021). Advances in human immune system mouse models for angiogenesis studying human hematopoiesis and cancer immunotherapy. Frontiers in Maroto, R., & Hamill, O. P. (2007). MSCCA Regulation of Immunology, 11. https://doi.org/10.3389/fimmu.2020.61923 Tumor cell Migration and Metastasis. Current Topics in 6 Membranes, 485–509. https://doi.org/10.1016/s1063- 5823(06)59019-2 Kirchhammer, N., Trefny, M. P., Maur, P. a. D., Läubli, H., & Zippelius, A. (2022). Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor Folkman, J. (2002). Role of angiogenesis in tumor growth microenvironment. Science Translational and metastasis. Seminars in Oncology, 29(6Q), 15– Medicine, 14(670). https://doi.org/10.1126/scitranslmed.ab 18. https://doi.org/10.1053/sonc.2002.37263 o3605 Banyard, J., & Symons, M. (2003). Cell motility and invasion Shademan, B., Karamad, V., Nourazarian, A., & Avcı, C. B. assays. Humana Press eBooks, 129– (2021). CAR T cells: Cancer cell surface receptors are the target for cancer therapy. Advanced Pharmaceutical 140. https://doi.org/10.1385/1-59259-281-3:129 Bulletin, 12(3), 476– 489. https://doi.org/10.34172/apb.2022.051 Levin, E. R. (2011). MiniReview: Extranuclear Steroid Receptors: Roles in Modulation of Cell Functions. Molecular Endocrinology, 25(3), 377– 384. https://doi.org/10.1210/me.2010-0284 Carmon, K. S., Gong, X., Lin, Q., Thomas, A., & Liu, Q. (2011). R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proceedings of the National Academy of Sciences, 108(28), 11452– 11457. https://doi.org/10.1073/pnas.1106083108 Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013). The importance of Raf dimerization in cell signaling. Small GTPases, 4(3), 180– 185. https://doi.org/10.4161/sgtp.26117 Milograna, S. R., Ribeiro, M. R., Bell, F. T., & McNamara, J. C. (2016). Pigment translocation in caridean shrimp chromatophores: receptor type, signal transduction, second messengers, and cross talk among multiple signaling cascades. Journal of Experimental Zoology Part a Ecological Genetics and Physiology, 325(9), 565– 580. https://doi.org/10.1002/jez.2052 Hon, K. W., Abidin, S. a. Z., Othman, I., & Naidu, R. (2021). The crosstalk between signaling pathways and cancer metabolism in colorectal cancer. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.768861