APP Cancer I (from notes) Flashcards
Neoplasia
- abnormal growth of tissue resulting from loss of responsiveness to growth control signals
Proto-Oncogene (vs. oncogene)
- encode proteins which normally stimulate call proliferation
- altered forms of proto-oncogenes are oncogenes
Carcinoma
Cancer of epithelial origin
EX: lung, breast, prostate, bladder
Sarcoma
Malignant neoplasms of mesenchymal origin
EX: Fat, bone, muscle
Prefix meaning: hemangio
blood vessels
Prefix meaing: adeno
gland
Hyperplasia
increase in the number of cells
Dysplasia
- Abnormal tissue architecture
- Cells retain their function
- Some cellular and nuclear changes leading to loss of cell uniformity
Anaplasia
- Undifferentiated cells
- Variable in size and shape
- Numerous and atypical mitoses
- Lack of organized tissue architecture
Rhabdomyosarcoma is a tumor of?
Skeletal muscle malignant tumor
Benign
- Well-differentiated cells with preserved specialized features of the parent cells
- Usually well demarcated. Often encapsulated masses
- NO invasion of the surrounding tissue
- No distant metases
Malignant
- Lack of differentiation, anaplasia
- locally invasive, infiltrating
- Frequently present in distant metastases
Normal Cell Growth
- Bone Marrow myeloblasts
- Immune cells
- Epidermal cells
- Epithelial cells
- Regenerating tissues
- cell division TIGHTLY regulated by both growth promothing and inhibitory regulators
- Usually cell damage or disruptions of cell cycle leads to cell death (apoptosis)
Features of Cancer Cells
- self-sufficiency in growth signals
- insensitivity to growth-inhibitory signals
- evasion of apoptosis
- limitless replicative potential
- sustained angiogenesis
- ability to invade and metastasize
- Evasion of host immune response
Cell Growth Regulation involces these factors (5)
- Growth factors (PDGF, EGF)
- GF Receptors (Tyrosine kinase, EGFR - ERBB1, ERBB2 (HER2))
- Signal-Transducing proteins
- Transcription factors (change Gene expression)
- Cell cycle check points
Oncogene
- altered forms of proto-oncogenes
- sustained gain-of-function alterations in cancers
3 mechanisms of Gain-of-Function Alterations
- Point mutations
- Chromosomal rearrangements
- Gene amplifications
Mechanisms of oncogene activation
1) multiple copies of oncogene (called?)
2) gene amplification
3) point mutation
4) chromosomal translocation leading to overexpression
How can Chromosomal translocation cause oncogene activation?
- oncogene can be traslocated adjacent to a gene that is constituitivelly on (change in transcriptional control elements)
- or translocated to create a noval-fusion gene to create a Chimeric Protein
TGF-alpha in sarcomas – is an example of what kind of dysregulation? Another ex?
- overexpression of Autocrine Growth Factor
- PDGF in GBM (glioblastoma?)
Tumor Suppressor
- usually get inactivated
- can be epigenetically altered (environmental control)
- usually recessive (both alleles must be inactivated to lose function).
- When inherited they lead to familial cancers –> inherited cancers develop in multiple locations EXAMPLE: Retinoblastoma; p53
retinoblastoma gene
(recheck this)
- a tumor suppressor gene, codes for DNA-binding protein, present in every single cell
- usually controls cycle by preventing transition from G1 to S
- Hypophosphorylation means active –> this prevents activation of S-phase genes
- double deletion in each gene results in RB tumor (GF release results in Rb protein inactivation by cyclin-dependent phosphorylation)
APC
adenomatous polyposis coli gene encodes protein regulating cell proliferation and adhesion APC protein interacts with beta-catenin, which is a signaling molecule in the WNT pathway With WNT stimulation, APC releases beta-catenin, and beta-catenin translocates to the nucleus and activates genes promoting cell-cycle progression In colon cancer these cause polyps which will 100% turn into malignant tumors transformation associated with loss of second APC allele occur in majority of sporadic colorectal cancers
p53
Is a transcription factor Active in every single cell protects our cells –> called guardian of the genome normally bound to MDM2 genes under stress (hypoxia, UV) it is no longer bound to MDM2 gene which causes its degradation and short-half life active p53 leads to transcription of CDK inhibitor -p21 –> G1 growth arrest common in >70% of human cancers tetrameric transcription factor alterations usually in DBD
Li-Fraumeni Syndrome
is a dominant syndrome caused by p53 issues other factors that contribute to LFS: mutations of CHK2 gene polymorphism of WT p 53
Consequences of p53 mutations
altered does not bind to DNA, loss of function and dominant negative mutant and gain of function
ERBB1
Epidermal Growth Factor Receptor 1 truncated receptors in glioblastoma
Proto-oncogenes - Growth Factor Recptors
1) Mutated or truncated forms of the receptors so that they are constitutively on - ex:glioblastoma 2) Overexpression of growth factor receptors - ex: ERBB1 in squamous cell carcinomas of lung -ex: ERBB2(HER2) in breast cancer
Proto-oncogenes - Signal Transducing Proteins
Examples of 2nd messenger systems which may be altered in CA: 1) RAS 2) SRC 3) ABL 4) RAF 5) MAPK
Ras in cancer
- Encodes p21 G-protein, which transmits mitogenic signal through phosphorylation
- Point mutations (that affects GTP binding site/GTP hydrolysis) can cause RAS (and RAF-MAPK pathwy) to be constitutively active
- Most common abnormalities in human CA (particularly, pancreatic and colon)
ABL
Non-receptor tyrosine kinase promotes apoptosis in CML, translocation of chromosome 22 where it fuses with part of BCR gene –> this forms aberrant chromosome, and therefore aberrant protein
Chromosome Philadelphia
Formed as a result of ABL translocating to BCR gene and fusing, creating an aberrant chromosome 22
What does the BCR-ABL protein do?
This fusion protein retains in the cytoplasm Has high tyrosine kinase activity –> stimulates multiple pathways including RAS-RAF mitogenic cascade
What is MYC?
The most commonly involved TF in human CA EX: 1) overexpression in Burkitt’s Lymphoma 2/2 translocation to the chromosome 14 in close proximity to Ig gene 2) Gene amplification in lung and breast 3) Similar genes such as N-MYC and L-MYC are gene amplified in NEUROBLASTOMA and NSCLC, respectively
Examples of nuclear Transcription Factors
MYC MYB JUN FOS REL
Cell Cycle Regulation
Progression of cell cycle is driven by cyclins and cyclin-dependent kinases (CDKs) Cell cycle is tightly controlled by CDK inhibitors
Most common perturbations in cell cycle regulation are?
G1 to S phase transition 2/2: 1) overexpression of cyclin D in breast, liver, esophagus, and lymphomas 2) Amplification of CDK4 in melanomas, sarcomas, and glioblastomas
Tumor Suppressor Genes
Tumor suppressor genes code for Growth inhibitory signals –> INHIBIT CELL PROLIFERATION or stimulate apoptosis upon damage Inactivation of tumor suppressor genes can result an insensitivity to growth-inhibitory signals
What may cause an inactivation of tumor suppressor genes?
1) mutations 2) truncation 3) deletions 4) methylation (epigenetic changes) of the promotor
Mutations of tumor suppressor genes
- Must be recessive meaning two alleles must be altered in order to lose their function inherited forms
- contribute to familial cancers and develop earlier in age
Retinoblastoma Cancer
pediatric tumor deletion of Rb tumor suppressor gene
sporadic form: both mutations in Rb acquired after birth –> tumor frequency is low
familial form: 1 mutation is already inherited, and 1 more needs to occur after birth –> frequency of retinoblastoma is very high and tumors arise bilaterally
BRCA1
- tumor suppressor genes
- encode nuclear proteins involved in response to DNA damage and DNA repair
- germline mutations cause 85% and 50% increased risk of breast and ovarian cancers
BRCA2
- germline mutations lead to increased risk of breast cancer 80%, while ovarian cancers are not as common but still risk of 10%
- associated with increased risk 6% of male breast cancer
HNPCC
hereditary nonpolyposis colorectal cancer
- associated with defects in mismatch repair genes
xeroderma pigmentosum
increased risk of UV-induced skin cancers due to the defects in the nucleotide excision repair system responsible for removal of UV-cross-linked residues
ALK
- anaplastic lymphoma kinase
- ALK is a receptor tyrosine kinase preferentially expressed in the CNS and PNS germline
- activating mutations of ALK have been associated with familial neuroblastoma, which segregates as autosomal-dominant disease
- also occur in sporadic cases of neuroblastoma
**This would be an oncogene and an alteration in it will be beneficial to the cell
miRNAs
oncogenic miRNA target tumor suppressors tumor suppressor miRNA target oncogenes
How does deregulation of apoptosis cause cancer?
- Leads to survival/propagation of damaged, mutated cells
- reduced levels of CD95 result in inactivation of death-induced signaling complex by FLIP protein
Telomerase activity
shorten telomeres 60-70 doublings and then cells enter non replicative senescence Telomerases is an enzyme which maintains normal length telomerases upregulated in CA which allows for unlimited cell divisions
