Lab 10 - Oncogenesis 1 Flashcards
Oncogenetic transformation/Carcinogenesis- Definition and what does it results from?
The way a physiological cell changes into a cancerous cell
Result from the action of one or a combination of chemical, physical, biologic and/ or genetic insults to cells.
Stages of Carcinogenesis
1) Initiation
2) Promotion
3) Transformation
4) Progression
Initiation
Exposure of cells to appropriate doses of carcinogens, either by environmental factors or due to hereditary traits.
Results from an irreversible genetic alteration, most likely one or more simple mutations, transversions, transitions, and/or small deletions in DNA.
Promotion
Reversible stage, does not involve changes in the structure of DNA but rather in the expression of the genome mediated through promoter-receptor interactions
Transformation
Conversion stage when it’s transformed to malignant cells
Progression
Irreversible stage characterized by karyotypic instability and malignant growth.
Angiogenesis
Metastasis
Angiogenesis
Formation of new blood vessels. Stimulates growth, induce malignancy and induce metastasis
Metastasis
Is a pathogenic agent’s spread from a primary site to a secondary site within the host body.
Two phases of metastasis:
- Invasion and growth: invades the extracellular matrix:
- Detachment of tumor cells from each other
- Degradation of ECM and basement membrane
- Attachment of tumor cells to matrix components
- Migration of tumor cells/locomotion/intravasation - Spread, dissemination, metastasis
- lymphatic spread
- Diret seeding of body cavities and surfaces
- Hematogenous spread
- CSF spread
Molecular targets during the stages of oncogenesis include
Protooncogenes
Cellular oncogenes
Tumor suppressor genes
5 Cancer cell characteristics
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- They are tumorgenic
Warburg effect
Cancer cells obtain their energy through aerobic glycolysis and not oxidative phosphorylation
Does cancer cells induce autophagy?
Definition of autophagy
No
A process where the cell itself stops their own growth and cannibalizes their own organelles and membranes due to severe nutrient deficiency
What does the cancer cells do with the normal stromal cells
The cancer secretes signal proteins and proteolytic enzymes that alter the stromal structure. The stroma then secretes signal proteins that stimulate cancel cell growth and division. The stroma also secretes proteases that remodel the ECM in favour of the tumor
Cancer cells show mutations in genes that are important for
Mismatch repair
Nucleotide excision repair
Base excision repair
Maintence of which enzyme is one of the most important characteristics for cancer cells?
Telomerase
Cancer cells can elongate telomeres in two ways
- Telomerase: is an enzyme that uses RNA as a template to restore the telomeres
- Alternative lengthening of telomeres: elongates the telomeres by DNA recombination
Tumors are describes by terms derived from
Appearance of the neoplasm, tissue of origin and degree of differentiation
Classification of tumors according to biological properties
Benign, malignant, locally malignant/ semimalignant.
Oma, carcinoma and sarcoma - suffix
Oma: benign
Carcinoma: malignant of epithelial or glandular origin, most common. Sarcoma: malignant of mesenchymal origin (connective tissue)
Lipo, Leiomyo, rhabdomyo, osteo, chondro, adeno, cholangio – prefix
Lipo: adipose tissue Leiomyo: smooth muscle Rhabdomyo: striated muscle Osteo: bone Chondro: cartilage Adeno: glandular Cholangio: bile duct.
Classification of tumors by grade
Increasing abnormality to respect for the surrounding tissues increases the grade.
Classification of tumors by stage
Staging is a way of describing or classifying a cancer based on the extent of cancer in the body. Based on size and metastasis, from where it started and where it spread to. Ex: TNM staging.
TNM stands for
T: size of primary tumor
N: lymph nodes involved
M: metastasis.
Benign vs malignant tumor
Cancerous: Benign tumor is not cancerous while malignant is cancerous.
Growth rate: Benign has slow, malignant has fast growth.
Recurrence: Benign tumors is less likely to recur while malignant are more likely.
Protective sac: Benign tumors is surrounded by a protective sac that restricts its growth and makes it easier to remove, malignant tumors does not have this sac.
Treatment: Benign tumors respond well to treatment and prognosis is favourable.
Invasive: Benign tumors are non-invasive while malignant are invasive. Benign tumors can be serious if they are pressing a primary nerve, main artery or compress brain matter.
Metastasize: Malignant tumors can multiply uncontrollably, metastasize and invade surrounding tissue, this is not happening with benign tumors.
Malignant tumors are formed from abnormal cells that are highly unstable and travel via the blood stream, circulatory system and lymphatic system.
Apoptosis- Definition and why it happens
Programmed cell death (death of damaged cells). When a cell becomes mutated and does not repair itself, it can be sacrificed to prevent that mutation from being passed on to the next generation of cells. Causes cell to shrink, develop belbs, undergoes degradation of genetic and protein materials in the nucleus, and have their mitochondria breakdown, thus releasing cytochromes.
What happens if DNA repair fails?
P53 protein activated the transcription of pro-apoptotic genes like BAX and PUMA
What genes are activated when the amount of pro-apoptotic proteins outweight the amount of anti-apoptosis?
BAX and BAK
Role of BAX
Punches holes in the mitochondrial membrane, which makes the mitochondria leak cytochrome c which leads to a series of events that initiate the apoptosis.
Loss of p53 function leads to what?
DNA damage goes unrepaired, mutations accumulate in oncogenes and other cancer genes, and the cell goes in a path leading to malignant transformation.
Necrosis- Definition and Cause
Premature death of cells and living tissue. Caused by factors external to the cell or tissue, such as infection, toxins or trauma. Cells may swell or forms vacuoles on their surface, with interior structures either distending or shrinking rapidly, destroying the cell’s process and chemical structures.
Unregulated release of cytochrome and cell membrane’s phospholipid during necrosis causes what?
Immediate reactions in surrounding tissue, leading to swelling (inflammation) and edema.
Macrophage-cleaning occurs in apoptosis or necrosis?
Apoptosis
Where does oncogenes originate from?
Proto-oncogenes, which are genes involved in the four basic regulators of normal cell growth:
Growth factors, growth factor receptors, signal transduction molecules and nuclear transcription factors
When mutation occurs in proto-oncogenes
It can become an oncogenes, a gene whose excessively product can lead to unregulated cell growth and differentiation
How are the oncogenes activated?
Typically by gain-of-function mutation, gene amplification (increased number of genes), hypomethylation of oncogene’s 5’ region (increases transcription), or chromosome rearrangements that upregulate the oncogene
Oncogenes are typically found in which tumors?
Sporadic tumors
Most oncogenes induce growth through the
Receptor tyrosine kinase pathway
Less common pathways for oncogenes growth
WNT pathway
Notch pathway
JAK/STAT pathway
Tumor suppressor gene
Is a gene that protects a cell from one step on the path to cancer.
When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.
Categorization of tumor suppressor genes
- Inhibitors of mitogenic signaling pathways
- Inhibitors of cell cycle progression
- DNA repair factors
- Inhibitors of “pro-growth” programs of metabolism and angiogenesis
- Inhibitors of invasion and metastasis
- Enablers of genomic stability
Inhibitors of mitogenic signaling pathways
NF1 (neurofibromin-1): neurofibromatosis type 1, neuroblastoma, juvenile myeloid leukemia
NF2: neurofibromatosis type 2, schwannoma, meningioma
APC (adenomatous polyposis coli protein): carcinoma of the stomach, colon and pancreas
Inhibitors of cell cycle progression
CDKN2A: INK4A and ARF: melanoma and different carcinomas
RB (retinoblastoma protein): retinoblastoma
DNA repair factors
BRCA1 and 2: breast and ovarian cancers
MSH2 and 6, and MLH1: colon carcinoma
Inhibitors of “pro-growth” programs of metabolism and angiogenesis
VHL: von vippel lindau protein
Inhibitors of invasion and metastasis
CDH1: E-cadherin: gastric carcinoma and lobular breast carcinoma
Enablers of genomic stability
TP53: p53 protein: Li-Fraumeni syndrome and most human cancers
Function of microRNA
Inhibit RNA and protein-coding RNA molecules themselves. Regulate cellular processes; cellular proliferation, differentiation and survival. Some function as tumor suppressor genes (Let-7), while others function as oncogenes (Mi-372 and mi-373).
How does the tumor cells affect miRNA?
They exhibit dramatic changes in miRNA expression. Loss/silencing or overexpression of miRNA is observes in many tumors. May therefore promote abnormal tumor cell survival.
Angiogenesis is controlled by a balance between what?
Angiogenesis promoters and inhibitors.
Angiogenesis promoters:
Basic fibroblast growth factors (bFGFs), VEGFs, proteases
Angiogenesis inhibitors:
angiostatin and endostatin
Angiogenic switch:
Increased production of angiogenic promoters and/or loss of angiogenic inhibitors
Angiogenic switch activated by:
Lack of oxygen, mutations in TSGs or oncogenes, gain-of-function mutations in RAS or MYC (RAS-MAP kinase pathway).
What are the effects of angiogenic switch on the tumor?
1) Stimulate growth: delivery of nutrients induces the secretion of growth factors by endothelial cells, IGFs and PDGFs.
2) Induce malignancy: newly synthesized blood vessels have an irregular pattern of connection –> irregular blood flow within the tumor, hypoxia in several areas within the tumor, areas of hypoxia favours the growth of mutant cancer cells seeing as they are more suitable to survive under harsh conditions.
3) Induce metastasis: tumors have access to the circulatory system and are able to metastasize.
What leads to permanent inactivation of tumor suppressor genes?
Loss-of-function mutation in RB1, deletion of the gene, hypermethylation of it’s 5’ region
