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A Neoplastic mesenchymal cells derived from ________________ can never be benign.
Normal cell proliferation involves a multitude of very complex and carefully balanced arrays of _______________
What is the general function of Regulatory proteins in Normal cell proliferation?
-Initiation of cell division and proliferation when the cell is in need
-Cessation of cell division and proliferation once the need of the cell is met.
The intracellular organelles are replicated in __________ phase of Cell cycle, whereas DNA will not be duplicated until _________ phase after getting properly repaired in ____________ phase.
Increased rate of cell cycle in Labile cells is induced by ________________
increased concentration of growth factors or proto-oncongenes (e.g. during injury)
Explain how the Cell metabolism gets Altered in Growing cells (normal or neoplasia) compared to Quiescent cells:
-Glucose is taken up, undergoes Kreb's cycle & oxidative phosphorylation to produce end products: ATP + CO2
<Normal growing cells or Tumors>
-Glucose gets SHUNTED away from Kreb's cycle and instead gets used for generation of precursor carbon molecules useful for making Lipids proteins, nucleotides, amino acids, all required for GROWTH of the subcellular constituents. (ATP still made)
What is the purpose of Altering cell metabolism in Quiescent cells when they're undergoing normal growing or neoplastic process?
By altering cell metabolism Glucose and glutamines are able to now make Building blocks of proteins, nucleotides, amino acids, lipids that are essential in cells for growing / replicating.
In Quiescent cells, Glucose and glutamines are used up to generate end products of ___________________
In Normally growing cells or Neoplasias, Glucose and glutamines are used up to generate end products of ___________________
ATP + CO2
(normal products of Kreb's cycle)
Precursor Carbons + ATP
(Building blocks for protein synthesis, nucleotide, amino acid synthesis, Lipogenesis) required for cellular constituents replication.
In order for DNA to properly duplicate itself in S phase, there must be effective _________________
repair of DNA in G1 phase.
Genetic hypothesis of Neoplasia:
-Group of disorders that develop as a result of accumulation of sequential, non-lethal genetic lesions (chromosomal, gene mutations, epigenetic) that culminate in autonomous cell replication and subsequent alterations in cell differentiation
--> This is NEVER a reversible process.
Neoplasia is a (single/ group) disorders that develop as a result of accumulation of (lethal/ non-lethal) genetic lesions that culminate in ____________ cell replication and subsequent ______________.
-Alterations in cell differentiation
3 Major pathways in which mutations in genome of somatic cells can result in:
1. Activation of growth-promoting oncogenes
2. Inactivation of Tumor suppressor genes
3. Alterations in genes that regulate apoptosis
8 Hallmarks of Physiologic alterations in Neoplasia (Benign & Malignant):
1. Self-sufficiency in growth signals (independence)
2. Insensitivity to growth-inhibitory signals
3. Altered cellular metabolism
4. Evasion of Apoptosis
5. Limitless replicative potential (immortality)
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to evade host immunity
List of Physiologic alterations in Neoplasia
(benign and malignant)
4 MAJOR types of Cell cycle Regulatory genes:
1. Growth-promoting proto-oncogenes
2. Growth-inhibiting tumor suppressor genes
3. Genes involved in DNA repair
4. Genes that regulate cell senescence or Apoptosis
(others: CDK, Cyclins, CDK inhibitors, etc)
Proto-oncogenes vs. Oncogenes:
-NORMAL genes that promote growth in cells (e.g. Growth factors)
-named so b/c it was discovered in cancer cells, but has nothing to do with tumor, until it gets mutated.
-Any gene that causes cancer
-Appears through non-lethal genetic lesions in either tumor suppressor gene or proto-oncogene.
Activating mutation of One of two alleles of ______________ end up in Neoplasia.
Activating mutation of BOTH alleles of ______________ end up in Neoplasia.
Tumor suppressor gene
Explain the mechanism of Initiation of Cell replication - enter G1 phase:
1. Binding of growth factor to G0 cell receptor
2. Transient activation of growth factor receptor
3. Signal transduction to nucleus
4. Activation of nuclear regulatory factors
5. Progression into cell cycle (G1)
CDKs are activated when ________________
CDKs are inactivated when ________________
bound to Cyclins
bound by CDK inhibitors
The whole process of CELL CYCLE (G1, S, G2, Mitosis, Cytokinesis) are regulated by 2 main classes of proteins:
2. Cyclin-dependent kinase (CDK)
List all types of Genetic lesions that foster Neoplasia::
-Inversions, insertions, deletion, point mutation
-Epigenetic alterations (affecting transcription/ translation)
Genetic lesions arise by 3 general factors:
1. Spontaneous (e.g. w/ age)
2. Environmental factors (e.g. carcinogens, viral)
3. Inherited (Familial)
What is Chromosomal aneuploidy?
Having an abnormal number of chromosomes in a haploid set, due to non-disjunction during meiosis.
Paracentric - chromosomal breakage does not include centromere --> both breaks occur in one arm of the chromosome
Pericentric - Breakage includes centromere and there's a break point in EACH arm.
Genetic lesions that affect _______________ lead to decreased / absent protein
Genetic lesions that affect _______________ lead to Altered, malfunction protein
-DNA itself (makes altered mRNA which makes abnormal protein)
Alterations in DNA or gene expression may lead to (3 consequences)
1. Decreased/ absent gene products
2. Abnormal gene products
3. Increased gene products
What effect does genetic lesion in Transcription process have on the Proteins synthesized?
What effect does genetic lesion in Translation process have on the Proteins synthesized?
BOTH decreased/absent protein
What effect does genetic lesion in DNA/Gene have on the Proteins synthesized?
Altered/ Abnormally functioning protein
What effect does Gene amplification have on the Proteins synthesized?
Increased protein synthesis
What type of Genetic lesion leads to synthesis of Increased protein?
Why are Neoplasias caused by Non-lethal genetic lesions? Why not lethal?
Lethal mutations make cells die, b/c they're lethal. Don't need to be worrying about them after they're gone.
However with Non-lethal mutations the mutations persist through gene expression processes and take effect on the proteins synthesized and consequently manifest malignancy in cell proliferation.
All neoplasias arise from accumulation of __________________ in a single cell followed by the __________________ of that altered cell as a result of __________________.
-Non-lethal genetic lesions
-selective, Darwinian advantage ("survival of the fittest")
___________________ is what allows the Clonal expansion of the altered cells in Benign and Malignant Neoplasias.
(genetic lesions allow Darwinian advantage by allowing cells to grow autonomously and to function much better than normal cells which they're derived from)
Define Darwinian advantage in Neoplasias:
A Phenomena in which Cancer cells survive much better and proliferate much faster than the cells it was DERIVED from.
(all due to genetic lesions that led to their selective advantage)
4 unique Characteristics of Cellular Neoplasia:
Most Neoplasias evolve by 2 ways:
1. Overexpression of oncogenes (dominant)
2. Loss of two or more tumor supressor genes (recessive)
Neoplasias in __________________ are intrinsically malignant. Give examples of these cancers:
BONE MARROW mesenchymal cells
- e.g. leukemia, lymphoma
Neoplasias in _________________ require additional non-lethal genetic lesions to develop into malignant phenotypes
Solid tissues like mesenchymal, epithelial tissues
(e.g. sarcomas, carcinomas)
Neoplasias in mesenchymal or epithelial tissues require _______________ to develop into malignant phenotypes
additional non-lethal genetic lesions/mutations
RB gene is a (proto-oncogene/ tumor suppressor gene)
TP53 gene is a (proto-oncogene/ tumor suppressor gene)
Tumor suppressor gene
Tumor suppressor gene
_____________ is an important tumor suppressor gene that is found in 60% of sporadic tumors.
_______________ modulates an on/off switch for transition from G1 into S phase of cell cycle.
____________ are what activate CDK enzymes that then phosphorylate the Rb protein
____________ are what activate CDK inhibitors which Inactivate the CDK that then prevents the phosphorylation of Rb protein
Growth factors, hormones (EGF), Proto-oncogenes
Growth inhibitors & Tumor suppressor genes (TGFB, p53)
Rb protein is tightly bound to E2F during ____________ phase of cell cycle.
G0 / G1
______________ is a crucial, promiscuous S phase cell cycle Transcription factor.
______________ event is what triggers the dissociation of E2F from Rb protein
Aside from Rb being hypophosphorylated, what is another event that's preventing the dissociation of E2F from Rb protein?
Histone deacetylase + Histone methyltransferase binding to E2F-Rb complex.
______________ is the "governor of cell cycle" and puts a brake on the cell cycle between G1 and S phase.
It is the Rb (gene/ protein) that is being phosphorylated.
("It's not the gene getting phosphorylated")
______________ is the "Guardian of the Genome"
When there is DNA damage the ______________ levels increase and regulate the G1-S checkpoint, preventing cells from proceeding to S phase.
Function of TP 53 gene:
Growth-inhibiting Tumor suppressor gene that increases expression of P53 protein when there's a damage in DNA --> activate CDK inhibitor to prevent the phosphorylation of Rb protein --> preventing the cell from proceeding from G1 to S phase.
Explain the consequence of mutation on TP53 gene:
No cell cycle arrest --> cells with genetic lesions/ mutations are allowed to proceed to S phase and replicate WITHOUT repair or senescence --> can lead to development of Neoplasia
Functions of P53:
activates genes that mediate cell cycle arrest in G1 --> prevents the Cyclin D hyperphosphorylation of RB and activates genes involved in DNA repair
--> "bides time" for appropriate DNA repair
IF the DNA repair does NOT occur in G1 phase, what happens?
p53 activates genes (BAX) that induce intrinsic cell apoptosis or senescence in the irreversibly damaged cell
____________ activates genes that mediate cell cycle arrest in G1
What happens when there is DNA damage in G1 phase?
increased expression of p53 protein --> Cell cycle arrest at G1 & activates DNA repair genes
(bides time for appropriate DNA repair to occur)
______________ activate bunch of proteins to try to repair the DNA damage in G1 phase.
How does the cell maintain the concentration of TP53 LOW in normal, healthy cells?
How is TP53 concentration RAISED in cells w/ damaged DNA?
TP53 gets bound by HDM2 protein --> suppresses the transcriptional activity of p53 and promotes its degradation
cells initiate synthesis of large quantity of P53 and alter the active confirmation --> dissociation of HD2 from P53 --> increased concentration of P53
In which situation related to P53 cause cells to go under Apoptosis?
In which situation related to P53 cause cells to go under uncontrolled, unregulated cell cycle?
When the repair of DNA by P53 gene was unsuccessful
When there is a mutation in P53 gene and is not able to regulate Rb protein, therefore no brake between G1 and S phase.
When _____________ , cells with DNA damage can proceed from G1 into S phase of cell cycle.
P53 is inactivated or is absent
Most common TARGETS for P53 alterations in human tumors:
1. mutations of TP53 gene
2. Increased HMD2
3. degradation of p53
TP53 mutations are present in more than _______% of cancer.
2 targets of Oncogenic human viruses (HPV, EBV) in tumor development:
In Li-Fraumeni syndrome, ______________ is inherited. Spontaneous loss of _____________ results in 25x increase in cancer predisposition.
One dysfunctional TP53 allele ;
2nd TP53 allele
3 features of Neoplasia that enable them to gain Darwinian Advantage:
1. Sustained Angiogenesis + lymphangiogenesis
2. Escape from immunity
3. Addition mutations to lead to acquired ability to invade + metastasize
Explain the mechanism of Acquired Tumor immunity:
Antigens expressed and loaded on MHC I Class molecules on surface of tumor cells are recognized by T-cells --> T-cells activated and differentiated by antigen-specific CD8+ T-cells and CTL.
Explain 3 Mechanisms of Immune evasion by Tumor cells:
1. Failure to produce tumor antigen --> Lack of T-cell recognition of tumor
2. Mutations in MHC genes or genes needed for antigen processing --> Lack of T-cell recognition of tumor
3. Production of immunosuppressive proteins or expression of inhibitory cell surface proteins --> Inhibition of T-cell activation
Tumor cell's acquired ability to invade and metastasize is due to altered ______________
adhesion molecules (E-cadherins)
What is the "additional mutation" that makes malignant neoplasias able to invade and metastasize?
-Mutation in Cell adhesion molecules (e.g. E-cadherin)
-Increased expression of ECM degradative enzymes + integrin interactions
Explain the consequence of mutation in E-cadherin:
Epithelial cells cannot be attached to each other, losing the ability to communicate through cell to cell interaction --> Dissociation from one another --> In a better position to invade to other tissues independently.
Explain the process of Invasion that occurs by malignant neoplasia
By genetic lesions, intercellular connections are broken --> Additional mutations trigger release of of enzymes (e.g. collagenase & proteases) --> Fibronectin & laminins produced --> Give cells the ability crawl / invade the basement membrane and penetrate into deeper tissue
4 mechanisms of Tumor spread:
1. Direct extension
2. Lymphatic spread
3. Hematogenous spread
4. Seeding into body cavities or onto surface
Why is Early diagnosis/ treatment of cancer cells so important for its prognosis?
During development of Neoplasia, the cells keep allowing mutations after mutations --> making MULTIPLE subclones of cancer cells --> "Genetically heterogeneous cancer"
Treating each different subclones of cancer cells make it extremely difficult to treat.
Describe the general phase changes that occur from normal cell to invasive carcinoma:
1. Normal / Non-proliferative cell
2. Proliferative disease (Hyperplasia)
3. Atypical hyperplasia (Dysplasia)
4. Carcinoma in situ
5. Invasive carcinoma (Cancer)
Most Carcinomas take _________ years to develop.
List all importances of understanding the molecular basis of cancer:
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Tissue/Organ injury and death
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