Neoplasia 2 Flashcards
Describe neoplasia.
-result of abnormality in cell cycle
-unlimited prolif
>irreversible unregulated autonomous
-result of heritable change in DNA of tumor cells
Describe what neoplasms often have mutations in.
- Defective DNA repair
- Self sufficient growth signal
- Insensitivity to growth inhibition
- Evasion of apoptosis
Describe senescence.
-resp to DNA damage, oxidative stress, telomere shortening, prolif cell undergo permanent arrest in G1 phase
-re-expression of telomerase = imp role in escape of tumor cells from senescence & immortality
Describe apoptosis VS autophagy.
- Apoptosis
-normal & pathogenic
-signals release cytochrome C from mitochondria = capases
-cancer cell require resistance to apoptosis by functional inactivation of p53 gene - Autophagy
-degrade cell own organelle within auto phagosome
-paradoxical role in tumor growth
-autophagy suppressed in many tumors & others have inc autophagy to enhance tumor cell survival under dec nutrient avail during therapy
Describe defective DNA repair.
-abnormal cell cycle checkpoint
-abnormal resp to DNA damage
-lead to genetic instability -> more mutation
Describe self sufficient growth signals.
- Proto oncogene
-normal
-prod are regulator of cell prolif & growth - Oncogene
-prod are oncoprotein = no regulatory elements
-expression = inc uncontrolled cell prolif (division)
-mutation dominant
-inhibit cell death
-dec cell differentiation
Describe oncogene example.
CKIT
-proto oncogene ckit encodes KIT = receptor tyrosine kinase w GF ligand
-mutation of ckit into oncogene = receptor always active w/o GF binding
-mutation in 20% K9 mast cell tumor
-production of:
>GF
>receptor for GF
>protein directly control entry of cells into cell cycle
*tyrosine kinase inhibitor used to treat K9 mast cell tumor ‘palladia’
Describe insensitivity to growth inhibition signals.
- Tumor suppressor gene
-inhibit cell prolif
-absent = cell insensitive to growth inhibition signal - Mutations are recessive
-need 2 independent mutations
-inherited in germ line
Describe an example of tumor suppressor gene.
P53
-encode p53 = DNA binding protein that stim genes involved in arresting cell cycle & stim DNA repair & apoptosis
-guardian of genome
-ineffective p53 = genetic instability
-mutation common in domestic animal
-inc tendency for DNA mutation & other genetic change to occur during cell division
Describe the evasion of apoptosis.
- Normal trigger for apoptosis
-DNA damage
-loss of nutrient/GF
-binding of death factor
-cytotoxic lymphocyte - Malignant cell better than benign cell
- Mutation dom or recessive
-ex: overexpression of Bcl2 = reduce apoptosis
Describe the therapeutic implications of the molecular basis of cancer.
-cancer treated using cytotoxic drugs or radiation therapy = neither discriminate normal VS tumor cell -> non selective cell killing has side effects
-mutation & other defects used to stratify patients for treatment or prognostic purposes
-WGS (whole genome seq) = ID all mutation in tumor & target specific driver mutations
-individualized cancer therapy
Describe clonicity in neoplasms.
-neoplasms are clonal = evolution of malignancy
>become heterogenous over time bc genetic instability
-progression/transformation:
A) dysplastic -> neoplastic
B) benign -> malignant
Describe tumor cell progression & effect of therapy.
Describe invasion.
in situ = not invaded BM yet (cancer at diff stages
-malignant tumor dont respect anatomic boundaries
>invasion is a prerequisite for metastasis
-invading cells must:
1. Overcome passive growth (mechanical) pressure: loss of contact inhibition
2. Loosen cell junctions
3. Penetrate BM & ECM via enzymatic destruction (collagenase, matrix metalloproteinases)
4. Migrate actively - stim by GF & cleavage prod of ECM
Describe epithelial mesenchymal transition.
- Loss of intercellular adhesion structures
- Enhanced expression of proteases
- Acquisition of migratory capabilities
- Reduced expression of epi cytokeratins & de novo expression of vimentin (mesenchymal cell marker)
Describe the metastatic cascade - tumor dissemination.
*most die from turbulence, oxygen toxicity, leukocyte attack, unfavorable nutritional environment, lack of GF
1. Tumor grows locally
2. Genetic & epigenetic changes -> metastasize
>lymph vessels
>blood vessels
>dissemination thruout bod cavity
Describe antitumor effector mechanisms.
-immunosurveillance = IS capable of recog Ag expressed on tumor cell & attack
-immunosuppressed ppl have greater prevalence of neoplasia
-2 types of IR determined by host & tumor Ag
1) innate IR
>1st line defense
>NK, Mac
>dont require Ag-specific priming
2) adaptive IR
>DC to capture tumor Ag & display on MHC
>cell mediated - most effective anti tumor defense (CD8 T cell)
>humoral - T helper & B cells
Describe the evasion of the IR.
-loss or mask of tumor specific Ag
-altered MHC expression
-tolerance - esp if Ag is shared w normal tissue
-immunosuppression - Fas ligand stim apoptosis of binding T cells
Describe macrophages phenotype & cancer.
-M1 & M2 = key regulator during cancer progression
-neoplastic cells promote polarization of M1 to M2 macs (TAMS) - poor prog in tumors
>prognostic bio marker ?
>therapeutic target ?
-M2 =
>promote motility of cancer cells in invasion areas
>promote metastasis in stromal & perivascular areas
>stim angiogenesis in avascular & peri necrotic hypoxic areas
