FPP-Week 2 Flashcards
Benign vs Malignant Tumors
Benign: “-oma”, resemble normal tissue, slow growth, encapsulated
Malignant: “carcinoma or sarcoma”, can look very different, variable growth rate, invasive, metastasize
Types of cell origin on Tumors
Epithelial: endo/ectoderm, adenoma or adenoCARCINOMA
Mesenchymal: mesoderm, lipoma or lipoSARCOMA
Hematolymphoid: always malignant, leukemias, lymphomas
Melanocytes: neural crest, nevus (mole) or melanoma
[[Teratomas: multiple germ layers]]
Tumor-like conditions
Hamartoma: mass or disorganized mature tissue (developmental issue)
Choriostoma: ectopic tissue in wrong location
Dysplasia
Disordered growth of epithelium
histologic dx
severe= carcinoma in situ (doesn’t extend past basement membrane)
Metastasis
criteria for malignancy
Basal cell carcinoma and gliomas do NOT metastasize
Hematogenous (via veins)- common for sarcomas, usually to liver, lung, vertebre
Lymphatics: common for carcinomas, sentinel nodes
Seeding body cavities: usually peritoneal,, ovarian cancer
Tumor Stage
TMN system
tumor size
nodal involvement
metastasis
CAR-modified T cells
fusion protein of tumor-specific antibody with co-stimulatory factors on T-cells, so when antibody binds tumor cell, the T-cell activates and kills the tumor
HER2/Neu (ERB B2)
Oncogene
abnormal constitutive activation (usually overexpression)
growth factor receptor-> tyrosine kinase
amplification in breast CA, poor prognosis, predicts estrogen therapy failure
Trastuzumab= antibody against HER2
c-KIT
oncogene
growth factor receptor-> tyrosine kinase
point mutation in GISTs (gastro intestinal stromal tumors)
Imatinib mesylate= tyrosine kinase inhibitor
RAS
oncogene family
Point mutations, 15-20% of all tumors, most common
K-RAS= colon CA
also pancreas and lung
GTP-binding proteins with reduced GTPase activity, which keeps them in active form (downstream of growth factor receptors)
c-ABL
Oncogene
translocation (9,22), Philadelphia chromosome, makes bcr-abl fusion-> constitutively active-> tyrosine kinase activity
CML- Chronic Myelogneous Leukemia
and ALL
MYC
Oncogene
transcription factor, activates genes
C-MYC= continued expression (Burkitt Lymphoma)
N-MYC= amplification (neuroblastoma)
Cyclin D1
Oncogene
cell-cycle regulator
activates CDK4 which phosphorylates Rb, which G1->S
translocation (11,14), Cyclin D1-IgH fusion, overexpression
Mantle Cell Lymphoma
p53
Oncogene
Causes cell cycle arrest and initiation of apoptosis
“first hit”= inherited, “second hit”= acquired
Li-Fraumeni Syndrome= inherited mutated p53= higher risk of cancers
Rb
Oncogene
encodes tumor suppressor protein, cell-cycle regulator
mutations cause uncontrolled E2F activation-> cell growth
Retinoblastoma and osteosarcoma
Familial Adenomatous Polyposis (FAP)
1000s of mucosal polyps in colon
potential to transform into cancer
Mutation of APC gene on chromosome 5q21
-> B-catenin accumulation (2-hits reqd)
BAX
oncogene
Pro-apoptotic
BCL-2
oncogene Anti-apoptotic overexpressed in many lymphomas translocation (14;18): IgH-bcl2 fusion= Follicular Lymphoma
SIS
Oncogene
overexpression-> astrocytoma, osteosarcoma
Carcinogens
Alkylating agents (electrophilic)
polycyclic aromatic hydrocarbons (need to be P450 activated, can have inducible form)
UV and ionizing radiation
Microbes (many)
Oncogenic Microbes
Viral genome integration:
-HPV, EBV, HepB
Burkitt Lymphoma= EBV
Stimulation of inflammatory response and regeneration:
-HepB,C, H pylori
H pylori= gastric adenocarcinoma and MALTomas
Regular vs Tumor angiogenesis
Regular: hypoxia->up VEGF,FGF,MMP->budding growth of capillaries->then down VEGF, up PDGF, Ang, TGFb
Tumor: hypoxia->up VEGF, PDGF->macrophages->EGF, MMP9, VEGF->disrupt ECM->budding of new capillaries->more VEGF, no resolution->weak, leaky, disorganized vessels
Also loosely attached pericytes and gaps in capillaries, fewer lymphatics, higher pressure
Angiogenic switch
The change that allows hyperplastic cells to transform into tumors
signals->mast cells and macrophages->MMP-9->disrupt ECM, release bound VEGF->make blood vessels
more vessels/VEGF=more aggressive tumor
Angiogenesis activators/inhibitors
activators: VEGF (makes leaky vessels, target of most therapy), FGF, PDGF
inhibitors: thrombospondin, angiostatin, endostatin
HIF-1
hypoxia sensor
normoxia->bound to VHL and degraded
hypoxia-> activates genes (VEGF)
VHL disease-> constitutively actives hypoxia genes (tumor risk)
Log-Kill
constant dose kills a constant fraction of tumor cells
need log-kill of 2-4 to be effective, and need 4-12 cycles
Need to balance frequency to allow normal cells to recover but not the tumor cells
Class I cancer drugs: Cell-cycle non-specific
alkylating agents, non-specific cytotoxiticy
Mechlorethamine
Carmustine
Class II cancer drugs: cell-cycle specific
Target a specific phase of cell cycle Frequent dosing G1: Prednisone S: Cytarabine, fluorouracil, Methotrexate, Mercaptopurine, Hydroxyurea G2: Bleomycin, Etoposide, Paclitaxel M: Vinblastine, Vincristine
Class III cancer drugs: cell-cycle specific, phase non-specific
Cytotoxic to all but G0 Single large doses Alkylating agent: cyclophosphamide Misc: Cisplatin Antibiotic: Doxorubicin
Lynch Syndrome (HNPCC)
Mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM genes
Increases risk of colorectal and other cancers
Mismatch repair gene defects lead to microsatellite instability (nucleotide repeats)
Path: lymphocytic infiltrate, Crohn’s rxn, Mucinous, Signet ring, Medullary pattern
Microsatellite instability also caused by somatic mutation in BRAF->hypermethylation of MLH1
Factor 5 Leiden
most common inherited predisposition for thrombosis
mutation in protein C (which is anti-coagulant, cleaves factor V, VIII)
Antiphospholipid antibodies
acquired autoantibodies against PL complexes
increases thromboses
Shock
systemic hypoperfusion hypovolemic cardiogenic septic (warm, flushed,, gram+ bacteria) neurogenic anaphylactic (IgE)
