Neoplasia & Immunodeficiency Syndrome Flashcards
Define Tumor and neoplasm
Tumor: Abnormal swelling, which can be benign (non-cancerous) or malignant (cancerous).
Neoplasm: An abnormal mass of tissue with excessive and uncoordinated growth that persists even after the initial trigger is removed.
What are the features of neoplasm and Neuplasia and Cancer
Key Features of Neoplasms
Purposeless Growth: The growth serves no functional purpose.
Progressive Growth: The tumor continues to grow over time.
Parasitic Growth: The growth disregards the body’s needs and consumes resources.
Aberrant Cell Growth: Imbalance between cell division (mitosis) and cell death (apoptosis).
Clonal Evolution: Tumor cells evolve through mutations.
Differentiation (Grading): The extent to which tumor cells resemble normal cells.
Neoplasia
The process of tumor formation.
Cancer
Refers to malignant tumors that invade surrounding tissues and can spread to distant sites (metastasis).
What’s Teratoma?
A teratoma is a neoplasm arising from pluripotent germ cells that can contain a diverse range of tissue types derived from more than one of the three germ layers: ectoderm, mesoderm, and endoderm.
What are the types of tumor?
Types of Tumors
Hamartoma: Non-cancerous, disorganized growth of native tissue cells.
Choristoma: Non-cancerous growth of normal cells in an abnormal location.
Difference Between Hamartoma and Choristoma:
Hamartoma: Disorganized growth in the original tissue.
Choristoma: Normal cells in an ectopic (wrong) site.
Teratoma:
What are the hallmark of cancer
Self-Sufficiency in Growth Signals
Cancer cells can grow without the need for external signals that normal cells require for growth.
Example: Mutations in growth factor receptors can cause continuous activation, leading to uncontrolled cell proliferation.
Insensitivity to Growth-Inhibitory Signals
Cancer cells ignore signals that normally inhibit cell growth.
Example: Mutations in tumor suppressor genes like RB or TP53 remove these inhibitory controls.
Altered Cellular Metabolism
Cancer cells often shift their energy production to aerobic glycolysis, known as the Warburg effect, to support rapid growth.
Example: Increased glucose uptake and lactate production even in the presence of oxygen.
Evasion of Apoptosis
Cancer cells avoid programmed cell death, allowing them to survive longer than normal cells.
Example: Mutations in genes regulating apoptosis, like BCL-2, lead to resistance to cell death.
Limitless Replicative Potential (Immortality)
Cancer cells can divide indefinitely, unlike normal cells that have a limited number of divisions.
Example: Activation of telomerase enzyme maintains telomere length, allowing endless replication.
Sustained Angiogenesis
Cancer cells stimulate the growth of new blood vessels to supply the tumor with nutrients and oxygen.
Example: Overexpression of VEGF (vascular endothelial growth factor) promotes blood vessel formation.
Invasion and Metastasis
Cancer cells can invade surrounding tissues and spread to distant sites in the body.
Example: Changes in adhesion molecules like E-cadherin and increased activity of enzymes like matrix metalloproteinases help in breaking through tissue barriers.
Evasion of Immune Surveillance
Cancer cells develop mechanisms to avoid detection and destruction by the immune system.
Example: Expression of proteins that inhibit immune responses, like PD-L1, helps cancer cells evade immune attacks.
List the Examples of Cancer Genes
RB Gene and RB Protein: RB gene mutations disrupt cell cycle control, promoting uncontrolled cell growth.
TP53 and p53: TP53 gene mutations prevent the p53 protein from inducing apoptosis, aiding in cell survival.
MYC: MYC gene amplification leads to increased cell proliferation and growth.
What are the characteristics to enable or enhance this hallmark
Cancer-Promoting Inflammation
Chronic inflammation can lead to a microenvironment that supports cancer development and progression.
Genomic Instability
An increased rate of mutations in cancer cells creates genetic diversity, allowing them to adapt and evolve.
Explain how cancerous cells become Self-Sufficiency in Growth Signals
Cancer cells become self-sufficient in growth signals through mutations that enable them to bypass normal regulatory mechanisms. These mutations can occur at various points in the growth signaling pathway, including growth factors, growth factor receptors, and downstream signaling proteins
Growth Factors: Autocrine Stimulation:
Some cancer cells produce growth factors to which they themselves are responsive.
Paracrine Stimulation:
Tumor cells can induce surrounding stromal cells to produce growth factors that support tumor growth.
Growth Factor Receptors
Growth factor receptors can become oncogenic through various mutations or overexpression.
Overexpression:Mutations and Gene Rearrangements:
These can cause receptors to become constitutively active, meaning they send growth signals even without growth factors.
Downstream Signal-Transducing Proteins
Mutations in proteins that transmit signals from growth factor receptors to the nucleus can also drive cancer growth.
RAS Protein:
RAS mutations lead to continuous signal transmission for cell growth.
ABL Protein:
ABL mutations can lead to uncontrolled growth signals
What are Oncoproteins, Oncogenes, Proto-Oncogenes
Proto-Oncogenes: These are normal cellular genes that promote cell proliferation under controlled conditions.
Oncogenes: These are mutated or overexpressed versions of proto-oncogenes that function independently of normal growth-promoting signals, driving increased cell proliferation.
Oncoproteins: Proteins encoded by oncogenes that drive cancer cell proliferation. These proteins may arise from various genetic aberrations.
What are the Key Mutations Leading to Sustained Proliferation
Growth Factor Receptors
EGF Receptor Tyrosine Kinase Activation: Point mutations in EGF receptor can activate this kinase (e.g., lung cancer).
HER2 Receptor Tyrosine Kinase Activation: Gene amplification of HER2 receptor leads to its activation (e.g., breast cancer).
JAK2 Tyrosine Kinase Activation: Point mutations in JAK2 kinase (e.g., myeloproliferative neoplasms).
Nonreceptor Tyrosine Kinases
ABL Activation: Chromosomal translocation creates a BCR-ABL fusion gene (e.g., chronic myeloid leukemia, acute lymphoblastic leukemia).
Downstream Signaling Molecules
RAS Activation: Point mutations in RAS lead to its activation (e.g., many cancers).
PI3K and BRAF Activation: Point mutations activate these serine/threonine kinases (e.g., many cancers).
Transcription Factors
MYC Expression: MYC, a master transcription factor, is increased by chromosomal translocations (e.g., Burkitt lymphoma), gene amplification (e.g., neuroblastoma), and increased activity of upstream signaling pathways (e.g., many cancers).
Cell Cycle Regulators
CDK4/D Cyclin Complexes: Mutations that increase the activity of these complexes promote cell cycle progression
What’s the Mechanisms of Aberrant Signaling in cancer?
Mechanisms of Aberrant Signaling
Point Mutations: Alter specific amino acids in proteins, leading to their constant activation.
Gene Amplifications: Increase the number of copies of a gene, leading to overexpression of its protein product.
Chromosomal Translocations: Chromosomal translocations occur when parts of two different chromosomes break off and swap places. This can create fusion genes that produce hybrid proteins with new, often harmful functions.
Increased Expression: Enhanced transcription (copying of DNA to RNA) or stability of oncogenes can lead to overproduction of oncoproteins
Examples of Oncoproteins and Their Mechanisms
Examples of Oncoproteins and Their Mechanisms
EGF Receptor Tyrosine Kinase: Point mutations activate this receptor in lung cancer.
HER2 Receptor Tyrosine Kinase: Gene amplification activates this receptor in breast cancer.
JAK2 Tyrosine Kinase: Point mutations activate this kinase in myeloproliferative neoplasms.
BCR-ABL Fusion Protein: Created by chromosomal translocation in chronic myeloid leukemia.
RAS Protein: Point mutations activate RAS in various cancers.
PI3K and BRAF Kinases: Point mutations activate these kinases in many cancers.
MYC Transcription Factor: Overexpressed due to translocations, amplifications, or increased upstream signaling.
CDK4/D Cyclin Complexes: Mutations increase the activity of these complexes, promoting cell cycle progression.
Cancer cells sustain proliferative signaling through mutations in proto-oncogenes, converting them into oncogenes that produce oncoproteins. These oncoproteins drive continuous cell proliferation by various mechanisms, including point mutations, gene amplifications, chromosomal translocations, and increased gene expression.
What are the Two primary tumor suppressor genes
Rb gene and the p53 gene.
These genes encode the retinoblastoma (RB) protein and the p53 protein, respectively,
Whats called the Governor of the Cell Cycle?
RB
The RB protein is crucial for controlling?
the transition from the G1 phase to the S phase of the cell cycle, where DNA replication occurs.
How do cancer cells evade growth suppressors?
In RB
Cancer cells can disrupt the normal regulatory function of RB through several mechanisms, leading to uncontrolled cell proliferation.
Loss-of-Function RB Mutations
Mutations in the RB gene can result in the production of a nonfunctional RB protein that cannot bind to E2F transcription factors. Without functional RB, there is no inhibition of E2F, and the cell cycle progresses unchecked, contributing to tumor development.
RB Mutation: Nonfunctional RB → E2F is not inhibited → Uncontrolled cell cycle progression.
CDK4 and Cyclin D Amplifications
The genes encoding CDK4 and cyclin D can be amplified or overexpressed in cancer cells. This leads to an increased formation of CDK4/cyclin D complexes, resulting in excessive phosphorylation and inactivation of RB. Consequently, E2F is continually released, promoting unregulated cell division.
CDK4/Cyclin D Overexpression: Increased RB phosphorylation → Inactivation of RB → Continuous release of E2F → Unchecked cell cycle progression.
Loss-of-Function Mutations in CDK Inhibitors
CDK inhibitors like p16/INK4a normally inhibit the activity of CDK4 and CDK6, preventing them from phosphorylating RB. Loss-of-function mutations in CDK inhibitors remove this inhibitory control, leading to increased RB phosphorylation and inactivation. This again results in the release of E2F and unregulated cell cycle progression.
CDK Inhibitor Mutation: Reduced inhibition of CDK4/6 → Increased RB phosphorylation → Inactivation of RB → Continuous release of E2F → Uncontrolled cell cycle progression.
Viral Oncoproteins
Certain viruses produce oncoproteins that can directly bind to and inactivate RB. For example, the E7 protein of human papillomavirus (HPV) binds to hypophosphorylated RB, preventing it from inhibiting E2F. This leads to the release of E2F and promotes uncontrolled cell division, contributing to the development of cancers such as cervical cancer.
Viral Oncoprotein (e.g., HPV E7): Binds hypophosphorylated RB → Prevents RB from inhibiting E2F → Continuous release of E2F → Unregulated cell cycle progression
Mechanism of RB Action
Hypophosphorylated RB
In its hypophosphorylated (low-phosphate) state, RB is active and performs its role as a tumor suppressor by binding to E2F transcription factors. E2F transcription factors are essential for the transcription of genes needed for DNA synthesis. When RB binds to E2F, it inhibits E2F’s ability to promote the transcription of these genes, thereby preventing the cell from proceeding to the S phase of the cell cycle, where DNA replication occurs. Essentially, hypophosphorylated RB acts as a brake on cell cycle progression at the G1/S checkpoint.
Active RB: Binds E2F → Inhibits transcription of DNA synthesis genes → Cell cycle arrest at G1/S checkpoint.
Hyperphosphorylated RB
When cells receive growth signals through growth factor receptors, these signals activate cyclin-dependent kinases (CDKs), particularly CDK4 and CDK6, which partner with cyclin D. These CDK-cyclin complexes phosphorylate RB. The phosphorylation changes RB’s conformation, making it unable to bind to E2F transcription factors. As a result, E2F is released and can activate the transcription of genes required for DNA synthesis, allowing the cell to enter the S phase and proceed with cell division.
Inactivated RB (hyperphosphorylated): Cannot bind E2F → E2F free to promote gene transcription for DNA synthesis → Cell cycle progression to S phase.
How do cancer cells evade growth suppressors?
In p53
Cancer cells often circumvent the tumor-suppressive actions of p53 through various mechanisms, leading to uncontrolled cell growth and survival.
Loss-of-Function Mutations
The majority of human cancers show biallelic loss-of-function mutations in the p53 gene. This means both copies of the gene are mutated, rendering the p53 protein nonfunctional. Without functional p53, cells lose the ability to undergo cell cycle arrest or apoptosis in response to DNA damage, allowing mutations to accumulate and contribute to cancer progression.
Loss-of-Function Mutations: Mutations in both copies of the p53 gene → Nonfunctional p53 → Failure to induce cell cycle arrest or apoptosis → Accumulation of genetic damage.
Li-Fraumeni Syndrome
Li-Fraumeni Syndrome is a hereditary disorder where patients inherit one defective copy of the p53 gene. These individuals have a very high risk of developing various types of cancers because the remaining normal allele is highly susceptible to somatic mutation, leading to a complete loss of p53 function.
Li-Fraumeni Syndrome: Inherited defective p53 allele → High risk of cancer due to loss of the second allele.
Viral Oncoproteins
Certain viruses produce oncoproteins that can bind to and degrade p53, effectively neutralizing its tumor suppressor functions. For instance, the E6 protein from human papillomavirus (HPV) binds to p53 and promotes its degradation, thereby preventing p53 from inducing cell cycle arrest or apoptosis.
Viral Oncoproteins: HPV E6 protein binds to p53 → Degradation of p53 → Loss of tumor suppressor function → Increased risk of cancer.
Mechanism of p53 Action
Activation by Stress Signals
p53 is a critical protein that responds to various cellular stress signals, such as DNA damage, low oxygen levels (hypoxia), and the activation of oncogenes. When cells experience stress, kinases such as ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are activated. These kinases phosphorylate p53, which stabilizes and activates it by preventing its degradation. Normally, p53 is kept at low levels in the cell through the action of the protein MDM2, which tags p53 for degradation. Phosphorylation of p53 by ATM/ATR inhibits MDM2’s ability to bind p53, thus protecting it from degradation.
Stress Signal Activation: DNA damage activates ATM/ATR kinases → Phosphorylation of p53 → Inhibition of MDM2-mediated degradation → Stabilization and activation of p53.
Cell Cycle Arrest and DNA Repair
Once activated, p53 induces the expression of several target genes, including p21, a cyclin-dependent kinase inhibitor. p21 binds to and inhibits CDKs, leading to cell cycle arrest at the G1/S checkpoint. This pause allows the cell time to repair DNA damage before proceeding with division. By halting the cell cycle, p53 ensures that damaged DNA is not replicated and passed on to daughter cells.
Cell Cycle Arrest: Activated p53 induces p21 expression → p21 inhibits CDKs → Cell cycle arrest at G1/S checkpoint → DNA repair.
Induction of Senescence or Apoptosis
If the DNA damage is too severe to be repaired, p53 can initiate cellular senescence or apoptosis. Senescence is a state of permanent cell cycle arrest, while apoptosis is programmed cell death. By driving damaged cells into senescence or apoptosis, p53 prevents them from continuing to divide and potentially forming tumors.
Senescence or Apoptosis: Irreparable DNA damage → p53 triggers senescence or apoptosis → Prevention of propagation of damaged cells.
