Exam 1 Flashcards
local cancer, not metastasizing, likely won’t metastasize, less problematic
benign
starting to spread or already spread to another site in body, problematic, kills
malignant
endoderm
epithelial
mesoderm
connective tissues, muscles, WBC, RBC
ectoderm
nervous, skin
why do epithelial cells often become cancer?
replicate a lot
cancer of epithelial cells that don’t secrete things
squamous cell carcinoma
cancer of epithelial cells that do secrete things
adenocarcinoma
tumor characteristics
progressive, monoclonal, and altered metabolism
explain how tumors can be progressive
normal –> hyper or metaplastic –> dyplsatic –> neoplastic –> metastatic
tissue with excessive number of cells
hyperplastic
tissue with cells in the wrong place
metaplastic
individual cells appear abnormal but basement membrane still intact
dysplastic
what falls between dysplastic and neoplastic?
adenoma, polyp, papiloma
invasive and cells spread
neoplastic
cells move to a new tissue
metastatic
monoclonal
single cells becomes cancerous and replicates into whole tumor
describe the experiment that explained why cancer is monoclonal and not polyclonal
only 1 band showing that only 1 type of Ig was present (all cells genetically identical and making exact same proteins versus if polyclonal would have multiple Ig
normal metabolism
glucose (anaerobic glycolysis) –>pyruvate (aerobic with O2)–> 36 ATP
hypoxia and metabolism
low O2- glucose –> pyruvate –> lactate
tumor metabolism
- not adequate blood supply
- hypoxic
- use a lot of glucose
warburg effect
cancer cells limit themselves to glycolysis even when O2 abundant
protooncogene
reg, normal gene has potential to turn into oncogene
oncogene
gene/protein that causes/drives cancer and prolif
mechanisms to activate a protooncogene to oncogene
1) retrovirus
2) point mutations
3) copy # increase
4) chromosomal translocations
5) miRNA
tumor suppressor genes functions
1) inhibitor of cell cycle
2) activators of apoptosis
3) inhibitors of protooncogenes
tumor suppressor gene losing function
LOH
1) mitotic recombination
2) during DNA replication
3) chromosomal nondisjunction
4) deletion of portion of chromosome
growth factor
protein made/secreted by one cell to tell another to prolif/mitosis/rep
paracrine growth factor signaling
2 cells near neighbors
endocrine growth factor signaling
2 cells not near neighbors
autocrine growth factor signaling
one cell makes own GF, telling to prolif
How does GF act as oncoprotein?
autocrine signaling- one cell makes own GF, telling to prolif (epithelial cell expressing GF receptor and due to mutation, expresses ligand)
EGFR
tyrosine kinase that tells cells to prolif ONLY when it binds EGF
describe EGFR/EGF in normal cell
EGF binds to 2 copies of EGFR, forces EGFR to homodimerize and turn on kinase activity (alone, EGFR can’t phosphorylate itself, but if close to another, can start phosphorylating)
autophosphorylation vs transphosphorylation
EGFR p EGFR but not itself so trans
ligand independent firing
even without EGF, EGFR can dimerize and turn on kinase activity through 5 mechanisms which result in losing ligand binding domain and locking into dimerization shape)
Why is having signaling evolutionarily favorable?
- regulation
- redundancy –> safety in having a lot of steps in case something goes wrong
- signal amplification
Ras signaling protogene to oncogene ex
mutations
- switch glycine to valine in Ras protein making Ras always on by abolishing GTPase fun
- miRNA mut, lose ability to reg Ras protein levels and inhibit Ras transcription (more Ras protein in cell)
- glycine to arginine making PI3K better at P PIP2
integrin signaling in normal cells
need 2 signals to prolif
1) GF signaling
2) integrin signaling
*gets survival signal by attaching to ECM, only prolif if ECM and GF present
ECM limits
number cells in body, attach or die
integrin signaling in cancer cells
anchorage independent growth so only need GF signaling
*gets survival and prolif signals without ECM
when integrins bind to ECM…
integrins cluster at focal adhesions occur so FAK can do transphosphorylation
integrin signaling steps
1) integrin clustering at a focal adhesion
2) focal adhesion kinase (FAK) will transphosphorylate
3) P FAK can bind to GRB2/SOS
4) Ras gets phosphorylated and activated by GRB2/SOS
PI3K is what type of signal
anti-apoptotic
Jak/Stat is a signaling pathway for
circulating cells
proteins involved in Jak/Stat pathway
GF cytokines, transmembrane receptor, Jak, STAT
Jak proteins
class of kinases that bind to transmembrane receptors, transphosphorylate when dimerization happens, P transmembrane receptor
STAT proteins
bind to P transmembrane receptor, get P, dimerize, go to nucleus to turn on expression of genes for proliferation
Beta catenin is involved in
GF signaling and binding cadherin
Wnt
type of GF that uses Beta catenin to turn on prolif (APC tumor repressor)
APC mutation
out of control proliferation in colon
no APC present
transcription ON all the time
colon cancer
- shed epithelial cells.. need to be repopulated
- stem cells located in crypts of colon
- stromal cells secrete Wnt GF to drive prolif of stem cells
Beta catenin in colon cancer
B-catenin off, prolif off
what happens if Wnt is not present?
- Wnt doesn’t bind frizzled receptor
- APC and friends bind P Beta catenin
- Beta catenin degraded and not acting as transcription factor
what happens if Wnt is present?
- Wnt binds frizzled receptor
- APC and friends bind frizzled
- Beta catenin enters nucleus and turns on transcription of genes for prolif
why is the cancer phenotype recessive?
need 2 mutated copies, multiple issues accumulate for normal to cancer
Rb is a
tumor suppressor gene associated with retinoblastoma
familial retinoblastoma
usually both eyes affected, multiple tumors, slightly younger avg age of onset
familial retinoblastoma genetics
at birth, one inherited mutated RB gene and one WT –> LOH –> disease
sporadic retinoblastoma
usually one eye
sporadic retinoblastoma genetics
at birth both WT –> random de novo mut –> LOH–> disease
LOH ways
1) mitotic recombination
2) during DNA replication
3) chromosomal nondisjunction
4) deletion of portion of chromosome
mitotic recombination
during mitosis, homologous chromosomes swap “homologous” genetic info
during DNA replication
sometimes DNA poly will “jump” from one homologous chromosome to another (part of mut copied into WT)
chromosomal nondisjunction
unequal pulling of chromosomes, possible for cell to get 2 mut copies of chromosomes
deletion of portion of chromosome
part of WT randomly deleted + mut —> missing WT copy of gene + mut version (2 mut in end)
VHL
ubiquitin ligase, kidneys and blood vessels
pVHL
involved in sensing O2 levels
H1F1a
transcription factor, turns on VEGF exp if O2 levels low
VEGF
tells blood vessel cells to prolif
problems with VEGF and HIFIa
cancer mut in pVHL that causes more VEGF
normoxia conditions and HIFIa
-HIFIa gets hydroxyl groups added
-pVHL can bind to HIFIa with hydroxyl groups
-pVHL adds ubiquitin to HIFIa
HIFIa gets degraded
normal cell cycle
- end M to R- cell taking in signals from environment and using signals to decide prolif or not
- R to M, cell no longer pays attention to external signals (committed)
cancer cell cycle
prolif without proper signals
cyclin/CDK levels
CDK proteins stable and cyclin fluctuate
external signals (integrin/GF) control which cyclin
D
cyclin + CDK required for
kinase activity
cyclin/CDK are proteins related to
DNA rep and mitosis
- P of histones –> loosening chromatin structure for DNA rep
- P of DNA poly subunits –> need for DNA rep
- P nuclear mem proteins –> lead to destruction –> allow M
no Rb is like
hyper P Rb (not bound DNA, transcription of cell cycle genes)
HPV causes
cervical cancer
- E7 protein from HPV adds ubiquitin to Rb –> degrade
- cell will then transcribe its cell cycle genes
