Chapter 7 Part 3 Flashcards
What is the stepwise acquisition of mutations that lead to the development of cancer?
- Initial carcinogen induced mutation
- mutation affecting genomic integrity
- additional driver mutations, acquisition of cancer hallmarks
- Additional mutations and emergence of subclones
Eight fundamental changes in cell physiology considered hallmarks of CA
- self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- altered cell metabolism
- Evasion of apoptosis
- Limitless replicative potential
- sustained angiogenesis
- ability to invade and metastasize
- ability to evade host immune response
What is a proto-oncogene?
growth promoter, involved in normal cell division and growth
What is an oncogene?
cancer-causing gene, promote autonomous growth
What allelic mutations are needed to promote neoplasia?
Conversion of one of two alleles from proto-oncogene to an oncogene, or loss of both tumor suppressor alleles
What is an oncoprotein?
resembles normal product of proto-oncogenes but contains mutations that inactivate internal regulatory elements
Mode of action of growth factor oncogene
Growth factors can acquire the ability to synthesize their own growth factors and cause autocrine stimulation
Mode of action of growth factor receptor oncogene
constiutive, growth-factor independent tyrosine kinase activity
EGFR1 gene product and associated CA
epidermal growth factor receptor, lung adenocarcinoma
EGFR2 gene product and associated CA
HER2 tyrosine kinase, amplified in breast carcinoma
ALK proto-oncogene activation and associated CA
translocation or fusion with EML4, associated with lymphomas and adenocarcinomas of the lung
Function of RAS proteins
signal transduction from RTKs to MAPK/PI3K pathways
Common point mutation result of RAS proteins
decreased GTPase activity resulting in constitutive pro-growth signals
Cancers associated with RAS protein mutations
colon, lung, pancreatic, bladder, kidney, melanomas, hematologic, pituitary, etc.
Result of activating BRAF mutation
downstream kinase and transcription factor activation
Mode of activation of BRAF and associated CAs
point mutation, melanomas, leukemias, colon carcinoma
ABL tyrosine kinase mode of activation and associated CA
translocation of gene from C9 to C22 - BCR-ALK gene product, acute lymphoblastic leukemias and chronic myelogenous leukemia
Main actions of MYC
activates genes involved in cell growth – protein synthesis, cell cycle progression; upregulates telomerase, reprogram somatic cells to stem cells
MYC mechanism of activation in tumor and associated CA
translocation, Burkitt lymphoma
CA associated with constiutive Wnt signaling
colon carcinoma
CA associated with constiutive HH signaling
meduloblastoma
Mechanism of activation in tumor of cyclin and associated CA
Translocation - mantle cell lymphoma and multiple myeloma
Amplification - breast and esophageal CA
Mechanism of activation in tumor of CDKs and associated CA
amplification or pt mutation, glioblastoma, melanoma, sarcoma
Main function of RB
tumor suppressor protein that binds E2F transcription factors in hypophosphorylated state to prevent G1/S transition
Main function of p53
tumor suppressor, acts through p21 to cause cell cycle arrest, causes apoptosis
Proto-Oncogene mutations result in…
excessive increase in one or more normal functions encoded in gene
tumor-suppressor mutations result in…
lack of growth inhibition, requires both alleles to be damages
mutations in genes that regulate apoptosis result in…
less death, enhanced survival
mutations in DNA-repair genes result in…
impaired ability to recognize and repair nonlethal genetic damage, can result in genetic instability
APC function
inhibit WNT signaling
APC familial syndromes and CAs
familial colonic polyps and carcinomas, carcinomas of stomach, colon, pancreas; melanoma
NF1 function
inhibit RAS/MAPK signaling
NF2 function
cytoskeletal stability
NF1 familial syndromes and CAs
neurofibromatosis type 1; neuroblastoma, juvenile myeloid lukemia
NF2 familial syndromes and CAs
Neurofibromatosis type 2; schwannoma, meningioma
PTCH function
inhibitor of HH
PTCH familial syndromes and CAs
Gorlin syndrome; basal cell carcinoma, medulloblastoma
VHL function
inhibitor of hypoxia induced transcription factors
VHL familial syndromes and CAs
Von Hippel Lindau syndrome; renal cell carcinomas
CDH1 function
cell adhesion, inhibition of cell motility
CDH1 familial syndromes and CAs
familial gastric CA; gastric carcinoma, lobular breast carcinokma
BRCA1 / BRCA 2 function
repair ds DNA breaks
BRCA1/2 familial syndromes and CAs
familial breast and ovarian carcinoma, carcinomas of male breast, chronic lymphocytic leukemia; sporadic CA development rare
MSH function
DNA mismatch repair
MSH familial syndromes and CAs
hereditary nonpolyposis colon carcinoma; colonic and endometrial carcinoma
WT1 function
transcription factor
WT1 familial syndrome and CAs
familial wilms tumor; wilms tumor, certain leukemias
What mutations are required to produce retinoblastoma?
two hits involving both RB alleles at 13q14
Function of PD-1
checkpoint protein on T cells that prevent T cells from attacking other cells in the body by binding to PD-L1
Mabs for PD-1
block binding of PD-1 to PD-L1 to bosst immune response to CA cells
CTLA4 function
downregulate immune response, upregulated on T cells after activation
Problem with CTLA4 Mab
serious and life-threatening side effects
PDE4 function
degrades cAMP in immune cells, prevents anti-inflammatory effects - psoriatic lesion development
Epigenome
factors other than DNA sequence that regulate gene expression
Methylation of DNA
causes changes in DNA structure and thus causes activation or silencing of genes
Histone acetylation
causes changes in chromatin regulatory complexes activating or silencing genes
miRNAs
function to modulate translation of mRNAs into their proteins, posttranscriptional silencing of gene expression
long noncoding RNA
modulate gene expression by binding to chromatin, restricting RNA polymerase access to coding genes
Warburg effect
increased lactose production in the presence of glucose via the glycolytic pathway, demonstrates “glucose hunger” of tumors
Is Warburg metabolism cancer specific?
No, it also occurs in growing cells (embryonic)
What does Warburg metabolism provide for a cell that oxidative phosphorylation does not?
metabolic intermediates needed for synthesis of cellular components
Role of PI3K/AKT in Warburg effect
upregulates glucose transports, glycolytic enzymes, shunts intermediates
Role of RTK activity in Warburg effect
upregulate enzymatic activity leading to a build up of glycolytic intermediates
Role of MYC activity in Warburg effect
upregulation of glutaminase and glycolytic enzymes
How can apoptosis be initiated?
intrinsic or extrinsic pathways
Which pathway of apoptosis is more commonly mutated in lesions?
intrinsic
What anti-apoptotic gene is most commonly overexpressed in B-cell lymphoma and why?
BCL2 due to a 14;18 translocation
How do cancer stem cells arise?
through transformation of a normal stem cell or acquired genetic lesions
What two lesions are commonly acquired in cancer cells that convey limitless replicative potential?
inactivated senescence signals and reactivated telomerase
Why is angiogenesis important?
required for growth of tumors
What triggers angiogenesis?
hypoxia via HIF-1a and VEGF
Actions of p53 for angiogenesis
induces synthesis of angiogenesis inhibitor thrombospondin-1
Actions of RAS, MYK, MAPK in angiogenesis
upregulate VEGF to stimulate angiogenesis
VEGF treatment
inhibitors can be used to prolong the clinical course but are not curative
What cells recognize tumor ags?
CD8 T cells
Classes of tumor antigens
products of mutated proto-oncogenes, tumor suppressor genes, overexpressed proteins, tumor ags produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins and cell-specific differentiation antigens
What types of cancer are immunocompromised pts at an increased risk for?
oncogenic DNA viruses
how may tumors avoid the immune system?
reduced expression of histocompatabilty antigens, immunosuppression expression, selective outgrowth of antigen-negative variants
HNPCC syndrome
hereditary nonpolyposis colon cancer; defects in mismatch repair systems leading to carcinomas of colon
xeroderma pigmentosum
defect in nt excision repair, increased risk for skin cancer due to inability to repair pyrimidine dimers
Defects in homologous recombination DNA repair system constitute what disorders?
Bloom syndrome, ataxia-telangiectasia, fanconi anemia
DNA damage in B and T lymphocyte tumors
occurs due to presence of products that induce genetic instability (RAG1, RAG2, AID)
CA enabling effects of inflammatory cells
release of factors that promote proliferation, removal of growth suppressors, enhanced resistance to cell death (anoikis), inducing angiogenesis, activating invasion and metastasis, evading immune destruction
oncogenic mutations
point mutations, chromosomal abnormalities, translocations, deletions, amplifications
How do balanced translocations contribute to carcinogenesis?
overexpression of oncogenes or fusion protein generation with altered signaling capacity
How do deletions contribute to carcinogenesis?
loss of tumor suppressor gene function, activation of proto-oncogenes
How do amplifications cause carcinogenesis?
increased expression and function of oncogenes
chromothrypsis
shattered chromosome reassembled in haphazard way
Translocation of CML
9;22
Translocation of AML
8;21 or 15;17
Translocation of burkitt lymphoma
8;14
Translocation of Mantle cell lymphoma
11;14
Translocation of follicular lymphoma
14;18
All-trans retinoic acid in acute promyelocytic leukemia
used to activate gene transcription to activate PMNs, PML+RARa translocation normally prevents gene expression with normal RA but ATRA allows for transcription
