cancer Flashcards by Lauren Parr

cellular processes that must be altered for cancer

evade apoptosis,
insensitivity to antigrowth signals,
self-sufficient growth signals,
sustained angiogenesis,
tissue invasion/metastasis,
limitless replicative potential

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oncogene

dominant behavior (only 1 mutation needed)
= gain of function --> remove regulatory signals to control activity

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tumor suppressor gene

normal gene,
when mutated in recessive fashion (loss of function)
lose ability to …

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warburg effect

cancer cells proven to have abnormally high rate of aerobic glycolysis
(use LOTS of glucose, release lots of lactate)
*in almost ALL cancer cells
–> enables use of PET scan to find tumors/cancerous cells

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isozyme (change) in bifunctional enzyme

PFKBP3 in cancer cells HIGHLY favors kinase activity
–> makes mostly fructose-2,6-biphosphate
(promotes glycolysis, esp. in hypoxic environment)

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18F-2-fluorodeoxyglucose

radioactive chemical used in PET scanning for finding tumors,
converted in body to 18F-2-fluorglucose-6-phosphate (= glucose analog)
(see Warburg Effect)

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PET scan

Positron emission tomography,
scan using radioactive glucose analog (18F-2-fluorodeoxyglucose) to image tumors
* basis: Warburg Effect (abnormally high glucose use in cancer cells)
** not useful for imaging bladder or kidney bc = excreted by urine, so always visualized there…

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WHY aerobic glycolysis in cancer cells (vs. oxidative phosphorylation)?

more than ATP, need NADPH for AA and nucleotide synthesis!

–> ox. phosphorylation yields more ATP,
but glycolysis yields ATP and NADPH

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Isozymes for metabolism, altered in cancer cells

Glut1–> Glut4 (cancer)
hexokinase1 –> hexokinase2
PFKFB2 –> PFKFB3
pyruvate kinase M1 –> pyruvate kinase M2

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Isozyme

isoform of an enzyme,
for unique functions/needs.
can be normal, but many swapped in cancer cells

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characteristics of Hexokinase2 (compared to HK1)

(HK2 = isozyme in cancer)
lower Km
higher ATP affinity
prevents apoptosis (unknown mechanism)

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characteristics of PFKFB3 (vs. PFKFB2)

(PFKFB3 = cancer isozyme)

strong preference for kinase activity
–> promotes fructose-2,6-biphosphate as product;
promotes glycolysis (*inducible in hypoxic conditions)

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p53

a transcription factor, induced by DNA damage.

action: maintain DNA integrity OR induce apoptosis (if too much damage)
target: TIGAR (inhibit glycolysis by lowering fructose-2,6-biphsophate)

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TIGAR

gene encoding Phosphofructokinase (“bifunctional enzyme”) w/ ONLY biphosphatase domain.
–> lowers conc. frustose-2,6-biphosphate
—> INhibit glycolysis
(*activated by p53 trans. factor)

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cancer cells have high need for glutamine bc…?

need glutamine for purine and pyrimidine synth,
(= nitrogen donor)
–> so high need for rapidly proliferating cell(s)

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Myc (oncogene) activates…

Glut1
Hexokinase 2
Pyruvate Kinase M2
lactate dehydrogenase
glutamine transporter
(all promote glycolysis)

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Src enzyme/pathway

signal cascade enzyme activated by RTKs and cytokine Rs, 
promotes invasion (by cancer cells)
-- incr. cell motility
-- decr. adhesion
-- incr. cell survival

Herceptin

HER2neu receptor antibody

-> RTK antagonist.
used for breast cancer chemotherapy

Gatekeeper Tumor suppressor gene

Controls cell growth by regulating checkpoints
or promote cell death

*LOH => cancer, ie: Rb

Caretaker tumor suppressor genes

guardians of cell genome,
protect against damage and mutations each day

LOH => cancer,
ie: BRCA1

Retinoblastoma (hereditary characteristics)

mutation in RB (gatekeeper) gene,
* requires 2 mutations to get tumor, BUT don’t have to be the same mutation.
very early onset, bilateral in hereditary cases

tumor burden

When a cancerous tumor interferes with normal body and cell functioning,
ie: crowding out healthy cells

3 categories of cancer (regarding genetics)

Sporadic - no germline mutation, no family pattern
Familial - family pattern, but no IDed germline mutation
Hereditary - germline mutation (AD inherited)

sequential nature of mutations

typically have multiple mutations in a single cell (do change behavior), before become malignant.
* critical step = when becomes malignant.

sporadic cancer

no germline mutation, no family history. * many mutations that build up over years, - - late age onset

familial cancer

significantly high prevalence of a cancer within a family, but no specific germline mutation. *no genetic testing for this* -- can be varied forms of a cancer

Rules of hereditary cancer

AD inheritance, specific germline mutation; usually early onset and bilateral (ie: both breasts). - if tumor suppressor, need 2nd hit mutation to get cancer.

leukocoria

condition where retina of person (usually child) appears white (not red) when flashed with light. indicates abnormal retina, ** tied to retinoblastomas**

Hereditary Retinoblastoma

germline mutation in RB gene (gatekeeper --> uncontrolled prolif), BUT need 2nd mutation to have disease; => tumors in retina, often multiple and bilateral, very early onset (sometimes before birth!)

Cancer 2 hit theory

Rule: need 2 mutations (both alleles) to get cancer. easier/earlier in inherited cancers bc: inherit 1 mutation in germline, --> only need second mutation to become malignant.

2 types of inherited colon cancer

1. FAP (familial adenomatous poliposis) -- APC mutation | 2. Lynch Syndrome (HNPCC) -- 4 muts possible (MLH-1 or 2, PMS2, MSH-6) --> all mismatch repair genes

FAP (familial adenomatous polyposis)

AD, inherited cause of colon cancer --> APC gene mut. --> 1000s of polyps (but variable), become cancerous if not removed early; Early onset (in teens) * can be mosaic;

Lynch Syndrome | aka: HNPCC (hereditary non-polyposis colon cancer)

mutation in mismatch repair genes (MLH1&2, PMS2, MSH6). early onset colon and endometrial cancers (avg age = 43) ---- also gastric, skin, urinary cancers! *more aggressive cancer Dx tests: microsatellite instability and Immunohistochemistry

Microsatellite instability

characteristic of Lynch Syndrome tumors, DNA slippage in short repeats not repaired (bc mut = mismatch gene) --> show diff. microsatellite sizes when run on gel

Li Fraumeni Syndrome

inherited mutation in p53 gene. high incidence of early onset cancers... ie: breast, adrenocortical, brain, and soft tissue cancers, etc.

hereditary breast cancer

mutation in BRCA1 (DNA repair) or 2 (double strand break repair), increased risk of breast and ovarian cancer. * esp. in Ashkenazi jewish women (CAN also occur in men)

clonal abnormality

when 2 or more cells have the same chromosomal abnormality -- characteristic of cancer

cytogenetic characteristics of cancer

1. acquired chromosomal abnormality 2. abnormality is clonal (in more than 1 cell) 3. abnormality limited to malignant tissue

t(9;22) chromosome abnormality

``` get novel (chimeric) gene with altered tyrosine kinase activity, --> chronic myelogenous leukemia ("CML"). ``` cytogenetic analysis: karyotype -- see Philadelphia chromosome (der. 22) and altered 9

Concerns about cancer treatment and stem cells

cancer stem cells are resistant to treatments, so may select out for more aggressive cancer to return! why? - do NOT replicate rapidly (not targeted by chemo/rad.) - resistant to drugs (pump out via ABC transporters!)