Cells and Cancer Flashcards
What are the 6 characteristics of cancer?
Acquire ability to replicate without signals Insensitive to inhibitory growth signals Evasion of apoptosis Limitless replication potential Sustained angiogenesis Tissue invasion
What is autonomous cellular replication?
performing the cell cycle to create 2 daughter cells with no control for environment, stimuli, or inhibitory proteins
What does the Platelet Derived Growth Factor do?
Matrix formation (increased numbers/activity of fibroblasts) Remodelling
What does Vascular Endothelial Growth Factor do?
Promotes Angiogenesis
What does Epidermal Growth Factor do?
Stimulates cellular proliferation (fibroblasts and epithelial cells)
What does thrombopoietin do?
Stimulates platelet formation
What does erythropoietin do?
Produced by kidneys to stimulate erythrocyte production
What does Colony Stimulating Factor do?
Stimulate myeloid lineage in haematopoiesis
How do cells receive stimuli from growth factors?
Receive signal on cell surface, which typically initiates a intracellular cascade initiating production of cyclins.
What colour would a tumour cell stain if haematoxylin and eosin was used and why?
It would be more blue within the cytosol due to higher metabolic activity of the ribosomes and presence of mRNA.
More erratic and blue nucleus
If tumour is larger, it would have presence of disorganized, dark blue nuclei following no particular pattern
What are common proto-oncogene cytoplasmic molecules?
Ras, B-RAF, Abl and Src (kinases)
How can mutations result in proto-oncogenes becoming oncogenes? Touch on types of mutations and their given impact.
deletion/point mutation- hyperactive protein made in normal amounts
regulatory protein mutation- normal protein in overproduced
amplification- overproduction of normal gene products
rearrangement- can move gene to different regulatory sequences resulting in hyper active fusion protein
What are examples of point mutation leading to an oncogene?
Ras- point mutation causes Ras to become hyperactive, dominant feature, found in 30% of tumours
BRAF- a kinase that transduces signals from cell surface, a point mutation results in hyperactive kinase. 50% of melanomas
What is an example of a deletion mutation leading to an oncogene?
EGFR- cell surface receptor, deletion mutation causes deletion of extracellular portion so the receptor is active even when EGF isn’t present
Found in non-small cell lung cancer
What is an example of a Gene amplification mutation leading to an oncogene?
ERB B2 (HER 2, human epidermal growth factor receptor 2) is a transmembrane receptor that receives signals, but is overexpressed in some tumours.
many copies of the protein are produced
found in 20% breast cancer, poor prognosis
What is an example of gene translocation mutation leading to an oncogene?
BCR gene on chromosome 22 is brought together with Abl gene, forming BCR/Abl hybrid.
Hybrid forms a hyperactive tyrosine kinase receptor, causing excessive leukocyte replication (occurs in chronic myeloid leukaemia)
Chromosome called the Philadelphia Chromosome
What are common tumour suppressor genes?
P53
Retinoblastoma
BRCA1
What causes the formation of a p53 related tumour?
Somatic mutation is TP53 (gene that produce p53 protein)
Found in half of all tumours
What is Li-Fraumeni Syndrome?
Inherited mutation of p53 tumour repressor
Increases risk of developing types of tumours
Related to germ line mutations
What process is the BRCA1 gene involved in in terms of its role in halting the cell cycle?
Involved in halting cell cycle for DNA repair
Chronic myeloid leukaemia accounts for 15-20% of adult leukaemia’s. Which molecular defect is associated with CML?
A chromosomal translocation resulting in the bcr-abl fusion
How can cells (mutating into cancers) avoid programmed death?
Increased expression of BCL-2
It inhibits apoptosis by regulating the mitochondrial membrane, therefore constantly inhibiting apoptosis
Inhibition of p53 to prevent stimulation of pro-apoptotic factors
How does the p53 gene initiate apoptosis in a normal cell?
Activates transcription of the Pro-Apoptotic Gene.
Pro-Apoptotic Gene then transcribes Bax
Bax works to create pores in the mitochondrial membrane, allowing for cytochrome C release.
Cytochrome C release then activate caspases (9 then 3).
Caspase 3 can then cause apoptosis of the cell.
What cancers involve BCL-2 translocation?
Lymphomas
How is unlimited cellular replication achieved in cancerous cells?
Hayflick limit is removed in 90% of cancers.
Telomerase enzyme is turned on/ upregulated, and is constantly elongating the telomeres of DNA, allowing for unlimited replication
How do cancer cells enhance their nutrient/oxygen delivery?
Early stages, they receive it via diffusion, but the cancer will grow, and diffusion will not be possible.
They acquire ability to release VEGF, and the hypoxic state of the tumour cells will release it, causing angiogenesis towards the tumour
What abilities does a tumour cell need in order to become metastatic?
Cells need to be able to disassociate from each other, invade basement membrane, migrate to other regions via entry and exit to circulation, and colonize in new location.
How do cells acquire metastatic capabilities in regards to migrating past junctions?
- Cell junctions need to be broken
- E-cadherin (present in epithelial tumours (80% of all tumours)) is lost in tumour cells as they progress
- Integrins form cell-ECM junctions, and altered expression is seen in cancer cells.
What aids in cancer cell migration through membranes?
Matrix Metalloproteases aids in stromal degradation helping move through basement membranes.
Examples:
MMP8, breaks down collagen.
Urokinase Plaminogen Activator (uPA) activates plasmin which promotes ECM & Fibrin degradation and is pro MMPs
How can understanding cancer mechanisms help in treatment?
We can create drugs that specifically target the genes/proteins that are acting inappropriately.
I.e. Herceptin drug to target ERBB2 gene to prevent amplification of HER2 receptor, to prevent overstimulation of cell replication.
In order for a cell to metastasise, it must breach the basement membrane. Which molecule would help to facilitate this invasive potential?
MMP8 will degrade the collagen IV in the basement membrane
What directly inhibits CDK activity?
Cyclin-Dependent Kinase Inhibitors
P21 -Cip (activated by p53)
P27 (Kip1)
P57 (Kip2)
What role does BCL2 play?
BCL (B-Cell Lymphoma) family regulates apoptosis
BCL2- On membrane of mitochondria, inhibits Bax and Bak activity on mito. membrane, preventing apoptosis (Bax and Bak would perforate mitochondrial membrane which allows release of Cytochrome C, a step in inducing apoptosis)
What phase of the cell cycle is dependent on mitogens?
G1 phase
What is the rule for naming epithelial cell benign and cancerous tumours? Give examples
Benign end in ‘oma’, cancerous ones end in ‘carcinoma’.
I.e. Glandular Epithelial: Benign- adenoma. Cancerous- adenocarcinoma
What is the rule for naming connective tissue tumours?
Benign ends in oma, Cancerous ends in sarcoma
How would you name benign vs cancerous lymphoid cells?
No benign lymphoid tumours (its blood)
Lymphoma (Non-Hodgkin or Hodgkin)
How would you name benign vs cancerous Haematopoietic cells?
No benign haematopoietic tumours (its blood)
Leukaemia
How would you name benign vs cancerous Primitive nerve cells?
Rare for benign
Retinoblastoma, Neuroblastoma etc.
How would you name benign vs cancerous Glial Cells?
No Benign
Glioma, i.e. astrocytoma
How would you name benign vs cancerous melanocytes?
Pigmented Nacvi (mole) vs. Malignant Melanoma
How would you name benign vs cancerous Mesothelium?
None vs. Malignant mesothelioma
How would you name benign vs cancerous Germ Cells?
Benign Teratoma vs Malignant Teratoma, seminoma
What are the examples of benign vs cancerous connective tissue tumours?
Smooth muscle- Leiomyoma vs. Leiomyosarcoma
Skeletal Muscle- Rhabdomyoma vs Rhabdomysarcoma
Bones forming- Osteoma vs Osteosarcoma
Cartilage-Chrondroma vs Chrondrosarcoma
Fibrous- Fibroma vs Fibrosarcoma
Blood Vessels- Angioma vs Angiosarcoma
Adipose- Lipoma vs Liposarcoma
What are the examples of benign vs cancerous epithelial cell tumours?
Covering epithelia- Papilloma, vs Papillocarcinoma
Glandular Epithelium- Adenoma vs Adenocarcinoma
Epithelium forming Organs- Adenoma, vs. (organ system name (i.e. renal, hepato) carcinoma)
What is Paraneoplastic Syndrome and why does it occur?
Syndrome brought on by cancers, in which the immune system trying to fight off cancer begins to attack self. Often causes neurological disorder.
I.E. Parathyroid Hormone-related Protein, carcinoma activates osteoclast activity, causing calcium to leave bones and enter blood, causing hypercalcemia
What are local effects of a malignant tumour?
Tumour may ulcerate and bleed (can cause anemia)
Palpable mass with pain
May obstruct hollow organs (i.e. bowel)
Describe the regularity of spread of a carcinoma in relation to lymphatics, blood, and transcoelomic (across peritoneal cavity)
Common, Common, stomach and ovaries
Describe the spread of a sarcoma in relation to lymphatics, blood, and transcoelomic (across peritoneal cavity)
Rare, Common (early), rare
Describe the spread of a melanoma in relation to lymphatics, blood, and transcoelomic (across peritoneal cavity)
Common (early), Common (late), rare
What is Neoplasia?
New, uncontrolled growth of cells that is not under physiologic control
What is Dysplasia?
Broad term that refers to the abnormal development of cells within tissues or organs
What is Metaplasia?
Transformation of one differentiated cell type to another differentiated cell type
What is Anaplasia?
Loss of the mature or specialized features of a cell or tissue
What is Hyperplasia?
Increase in the amount of organic tissue that results from cell proliferation
What is Hypertrophy?
Number of cells stay the same, but are of abnormal size (end stage heart failure)
What CDKI impacts the progression past G1?
P57 (Kip2)
Directly binds and inhibits Cyclin D/ CDK4/6
What CDKIs impact the DNA repair checkpoints?
P27 (Kip1)- Directly binds and inhibits Cyclins E & A/ CDK 2
P21 (Cip) - binds and inhibits all, but primarily CDK 2
P16 (Ink)- Inhibits CDK 6
What CDKI impacts the progression through chromosome attachment checkpoint?
P21 (Cip)- can inhibit kinase activity of CDK1
When looking at mutations in cancer, do oncogene mutations tend to be dominant or recessive?
Dominant
When looking at mutations in cancer, do tumour suppressor mutations tend to be dominant or recessive?
Recessive (except for p53)
Two-hit hypothesis, need to inherit mutation in both alleles.
How is a p53 mutation different from other tumour suppresors?
It is dominant negative, meaning recessive inheritance of the mutated gene will still result in faulty p53 genes.
Can tumour cells release MMPs?
Yes, but more commonly they stimulate MMP release by other cells (endothelial cells, macrophages, fibroblasts)
What is an example of a drug and its target, used in treating breast cancer?
Trastuzumab (herceptin) targets ERBB2 (HER2)
What is an example of a drug and its target, used in treating colorectal cancers or non-small cell lung cancers?
Bevacizumab targets VEGF
VEGF promotes angiogenesis, reducing blood supply to cancers can reduce their angiogenic capabilities, reducing nutrient/oxygen/immune cell supply to the cancer
What is an example of a drug and its target, used in treating chronic myeloid leukemia?
Imatinib targets ABL
Targeting and inhibiting ABL gene will prevent hyperactivation of the tyrosine kinase receptor
What is an example of a drug and its target, used in treating melanoma?
Vemurafenib targets BRAF
BRAF gene encodes Raf protein involved in tyrosine kinase intracellular activation cascade, preventing transcription of Raf will reduce activation
What is a pneumonic to remember drugs and their targets?
(Tr)eat her to (HER2)
(Be)autiful (VEG)etarian
(Ima)ges, en(ABL)ing her stop eating
(Ve)ry (M)ajestic ze(BRAF)ish
Trastuzumab (herceptin) targets ERBB2 (HER2)
Bevacizumab targets VEGF
Imatinib targets ABL
Vemurafenib targets BRAF