10/4 Flashcards
Epidemiology
Study of the distribution, determinants, prevention, and control of disease
Different Kinds of Cancer Epidemiology
- Analytic: cancer’s determinants in human pop.
Men have higher risk of cancer than females, may be due to height
- Molecular epidemiology: examination of biological markers of exposure, disease, and points in between
Exposure: cytokines, SNPs, FAs in blood
Disease: tumor Histology/differentiation, prostate specific antigen test
Points in between: breast tissue inflammation, DNA adducts, miRNA expression, DNA methylation
miRNA Biogenesis
- Transcription
- mRNA gets processed by DGCR8 and Drosha
- Export to cytoplasm by Exportin 5
- Dicer processing: cuts loop and adjacent mRNA, yields dsRNA, then acted on by helicase
- Strand selection by RISC
- Translational repression if good complementary mRNA to the ssRNA, cleave mRNA if total
Onco and tumor suppressor miRNAs
miR-221 and miR-222 tumor suppressor: loss results in erythroblastic leukemia, inhibits proliferation in erythroblasts, involves KIT
miR-221 and miR-222 onco: overexpression in aggressive CLL, thyroid/hepatocellular carcinoma, promotes cell proliferation and inhibits apoptosis in various solid malignancies, inhibits p27 that regulates cell cycle
miRNA act as Hormones
Released in exosomes or microvesicles while associated with RNA binding proteins, extremely stable
miRNA found in saliva, serum/plasma, urine, CSF
Move through blood to distant cells
Unknown receptors take up miRNA in muscle cells, cause apoptosis that leads to cachexia
miRNA Nomenclature
Species specific: hsa-, mmu-
miRNA indication: miR for mature, pri- and pre-miRNA for primary and precursors, MIR for genes
Primary is made from transcription, precursor is after DGCR8 processing, mature is after dicer
miRNA number: 181, 146
miRNA variant: a, b, c
miRNA allele: miR-181a1 and miR-181a2 since multiple copies of same allele
miRNA strand: 3p or 5p, 5p is at the stalk before the loop at the 5’ end of the miRNA
Telomeres and Telomerase
Telomeres: TTAGGG, bind different proteins at telomeres to prevent degradation and unwanted associations since one end hangs out
Telomerase: stem cells don’t shorten since have telomerase, a reverse transcriptase (TERT) that contains an RNA template (hTR)
Stem Cells
Unspecialized cells that lack tissue-specific differentiation and specialized function
Defined for their capacity of self renewal so divide and daughter cells contain same biological properties
Long lasting and normally quiescent but can proliferate to repopulate injured tissue
Cancer stem cells: dysregulation of normal self renewal pathways that involve cellular pathways like Wnt and tumor suppressor genes like p53
Form transit amplifying cells that gain additional mutations and lead to tumor growth/expansion but are incapable of long term maintenance of the tumor
Warburg Effect: Clinical Utility
Do PET scan wit 18-fluorodeoxyglucose (FDG) which is a nonmetabolizable compound
FDG concentrated in tumors, brain will also light up since uses a lot of glucose normally, can’t use FDG for brain cancer, also in bladder since piss out
Tumors are also glutamine hogs
Cells of the Tumor Microenvironment
- Fibroblasts: tumor initiation, growth, and invasion
- Adipocytes: adipokines increase tumor migration/invasion
- Tumor endothelial cells: leukocyte recruitment and tumor invasion/metastasis
- Pericytes: stabilize blood vessels, inhibit endothelial cell proliferation, maintain capillary diameter, regulate blood flow, provide endothelial survival signals
- Tumor associated macrophages: immune regulation, promote tumor cell growth/development
- Dendritic Cells: induce vascularity and involved in tumor immune-pathogenesis, have pro/anti tumor functions
- Mast cells: elaborate GFs, VEGF, MMPs, and chemokines
Promotes tumor development by disturbing the normal stromal-epithelial communication, facilitating tumor angiogenesis, releasing GFs, and inducing state of immunosuppression
Cancer Associated Fibroblasts
Activated by: GFs (like TGF-beta, FGF2, and PDGF), ECM professes, and chemokines
Activation leads to: cell proliferation, synthesis of ECM components like tenascin-C, various GFs, chemokines, and expression of alpha smooth muscle actin
Facilitate angiogenesis and make fibrosis (desmoplasia)
Increased deposition of collagen I and III, mediate inflammatory response through chemokines like monocytes chemotactic protein 1 (MCP1) and IL-1
Secrete MMPs and VEGF
Desmoplasia
Growth of the stromal component of the ECM that is associated with the tumor
Fibrosis that follows tumor, prominent at leading edge of a carcinoma
Cancer Associated Adipocytes
Delipidation to lose lipids, decreased expression of adipocytes markers, over expression of pro-inflammatory factors and ECM-related molecules
Adipocyte derived stem cells differentiate to generate adipose derived fibroblasts that express smooth muscle actin
Transition associated with profibrotic state and enhanced tumor cell migration
Help tumors develop chemo/radioresistance
Cancer Associated Endothelial Cells
Control leukocyte recruitment, limits effectiveness of host response against tumor
Express MMPs and TIMPs that influence tumor progression
Tend to form dilated, tortuous, and highly permeable vessels
Tumor Associated Macrophages
Help cell proliferate, remodel ECM, promote angiogenesis, aid tumor cells in evading immune response
Change over time-
M1 Macrophage: normal macrophage activity that leads to pro-inflammatory response
M2 Macrophage: produce cytokines like TGF-beta and IL-10 that promote tumor evasion of host immune response
Tumor Cell Invasion of the ECM
- Loosening of cell-cell interactions: E-cadherins function is lost
- Degradation of BM and ECM: tumor cells secrete proteolytic enzymes or have fibroblasts/inflammatory cells in the tumor microenvironment make proteases
Use MMPs, cathepsin D, plasminogen activators
MMP degradation liberates GFs bound to ECM, proteolytic products of collagen have chemotactic and angiogenic effects
- Attachment to new ECM components: normal cells die if lose interaction between integrins on basal surfaces that bind to lamins/collagens in BM
MMP activity in Bm generates novel receptor binding sites that tumors recognize, promotes invasion
- Migration and invasion of tumor cells: tumors propel through BM and proteolyzed ECM, different cell receptors converge on tumor actin cytoskeleton
Leaves microtrack behind trailing edge, can move as single cells or collective cells when well differentiated, use cross talk with fibroblasts and lymphocytes
Tumor Cell Spread through Blood
- Intravasation-
A. Active: Tumor associated macrophages release TNFalpha and chemokines
B. Passive: increased vascular permeability and increased interstitial pressure pushes tumors into the vessel
- Intravascular Survival: tumor cells aggregate into clumps with platelets and RBCs, protect from immune cells and enhance implantability of the clump to form a metastatic deposit, guide to site of inflammation/injury so easier to invade
Emboli: tumor cells in circulation activate/bind coagulation factors and form blood clots
- Extravasation: facilitated by factors released from primary tumor (TGF-beta and TNF-alpha), involves Selection cell adhesion and differential expression may account for homing
Metastasis Sites
- Anatomical location
- Vascular drainage of primary tumor site: first capillary available to intravascular tumor like colon cancer to liver
- Tropism of tumor for specific tissues: prostate cancer to bone, tumor cell Adhesion molecules prefer endothelial cells in one particular organ, chemokines may play a role, spleen and muscle rarely develop metastases
Common Sites of Metastasis
- Brain: lung, breast, melanoma, renal cell, colorectal
- Lung: renal cell, colorectal, melanoma, breast, sarcoma
- Liver: colorectal, pancreatic, estrogen receptor negative breast, lung, stomach
Gastrointestinal tumors access liver through portal venous system
- Bone: estrogen receptor positive breast, lung, prostate, renal cell, colorectal
Epithelial to Mesenchymal Transition (EMT)
Detachment of carcinoma cells from each other/BM is due to the loss of cell adhesion and the start of cell invasion is aided by the carcinoma cell losing the epithelial phenotype and adopting a more mesenchymal phenotype
Tumor cells at the invading interface more likely to undergo EMT than cells deep in the tumor
Once reach distant site reverse changes to go back to epithelial phenotype
E-cadherins and integrins expression decreased during EMT but E-cadherins present in adenomas
SNAIL and TWIST: Metastasis oncogenes that are TFs that support EMT, decrease expression of epithelial markers like E-cadherins and keratin, upregulate expression of mesenchymal markers like vimentin and smooth muscle actin
Microenvironment and EMT Signaling
Type 1 collagen binds to integrins
EGF, FGF, and HGF bind to tyrosine kinase receptor
Also TGFbeta and its receptor
E-cadherins Receptor degraded by MMP3, releases beta-catenin to make it available for transcriptional regulation
Biomarker Goals
Subclassify patients for individualized treatment
Benefits of treatment greatly outweigh toxicity risk
Reproducible
High sensitivity/specificity
Serum Tumor Biomarkers
- CEA: primarily for colorectal carcinoma
Also for GI, breast, lung, prostate tumors
Benign conditions- smoking, PUD, pancreatitis, cirrhosis - PSA: only for prostate tumors
Benign conditions- prostatitis, BPH, trauma, ejaculation - CA125: primarily ovarian carcinoma
Also endometrial, breast, lung, GI, liver, pancreas
Benign conditions- menstruation, pregnancy, fibroids, ovarian cysts, pelvic inflammation, cirrhosis, and others
Tumor associated glycoprotein, poor screening tool for ovarian cancer and is not a diagnostic tool, approved for screening for recurrent/residual disease
Tissue Biomarkers
Used as predictors of therapy efficacy, not disease prognosis
ER/PR: predicts response to hormonal/chemotherapy in breast cancer, get uneven staining since tumor is heterogenous genetically
HER2: predicts Response of blocking HER2 receptor therapy in breast cancer, nuclear oncogene amplification detected via FISH
CD117 (c-KIT): predicts response to targeted therapy with imatinib (a tyrosine kinase inhibitor)
CD20: in tissue sir on cells, predicts response 59 rituximab (monoclonal antibody) in patients with B cell lymphomas
Molecular Biomarkers
Chromosome: Philly chromosome (t9;22) predicts chronic myelogenous leukemia, Use receptor tyrosine kinase inhibitor BCr/Abl to limit proliferation
Lynch Syndrome: MLH1, MLH2, MSH6, PMS2 mutations increase risk for colon, stomach, and ovary carcinoma
Li-Fraumeni Syndrome: mutation in TP53 increases risk for breast carcinoma, acute leukemia, and other cancers
HPV: causes multiple types of squamous cell carcinomas
Molecular Biomarkers: Receptor Signaling
EGFR mutation so constitutively active has no treatment in lung adenocarcinoma, needs no GF since constantly work
Gefitinib: EGFR tyrosine kinase inhibitor, works in colon since no mutation in receptor
K-Ras: multiple signaling pathways, treat most downstream mutations like in ERK, antibody doesn’t work on mutated receptor
Tumor Specific/Associated Antigens
Tumor Specific: present mutant peptides from mutant cell proteins on MHC Class I Receptor, can get novel peptide splicing from proteasome
Tumor Associated: deactivation of embryonic genes not normally expressed in the differentiated cell
Overexpression of normal self proteins by a tumor cell changes density of self peptide presentation
Evasion of the Immune Response by Tumors
- Normally MIC expression leads to death from NK cells or T cells, tumors cleave MiC from their surface with a protease and the soluble MIC binds to NKG2D on lymphocytes
Soluble MIC undergoes receptor mediated endocytosis while tumor cell survives
- CD8+ cells are good at killing if express tumor antigens in MHC Class I Receptor, tumor cells downregulate MHC Class I receptors but are vulnerable to NK cells
- APCs are not activated by tumors and remain in immature state, don’t express costimulatory molecule B7 to activate CD8+ T cells, results in anergic T cells
- Release TGFbeta to limit immune response by negatively regulating TH1 cells and Cytotoxic T cells, upregulates Treg cells that secrete TGFbeta and IL-10 to limit lymphocytes
Monoclonal Antibodies against Cancer
Vaccination with tumor antigens kinda works, use tumor Specific antigens
Rituximab: for CD20 which is a B cell signaling receptor, treats Non-Hodgkin’s Lymphoma, conjugated to radionuclide to irradiate malignate B cells, radiation damages DNA and leads to cancer cell death
Bevacizumab: for VEGF and treats colorectal and non-small Cell lung cancer
Gemtuzumab: for CD33, treats acute myelogenous lymphoma, antibody is conjugated to a toxin, binds to tumor cell and is internalized, toxin cleaves from conjugate and creates dsDNA breaks that lead to apoptosis of cancer cell
