FPP-Week 2 Flashcards by Matt Doers

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

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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]]

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Tumor-like conditions

Hamartoma: mass or disorganized mature tissue (developmental issue)
Choriostoma: ectopic tissue in wrong location

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Dysplasia

Disordered growth of epithelium
histologic dx
severe= carcinoma in situ (doesn’t extend past basement membrane)

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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

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Tumor Stage

TMN system
tumor size
nodal involvement
metastasis

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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

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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

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c-KIT

oncogene
growth factor receptor-> tyrosine kinase
point mutation in GISTs (gastro intestinal stromal tumors)
Imatinib mesylate= tyrosine kinase inhibitor

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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)

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c-ABL

Oncogene
translocation (9,22), Philadelphia chromosome, makes bcr-abl fusion-> constitutively active-> tyrosine kinase activity
CML- Chronic Myelogneous Leukemia
and ALL

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MYC

Oncogene
transcription factor, activates genes
C-MYC= continued expression (Burkitt Lymphoma)
N-MYC= amplification (neuroblastoma)

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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

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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

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Oncogene
encodes tumor suppressor protein, cell-cycle regulator
mutations cause uncontrolled E2F activation-> cell growth
Retinoblastoma and osteosarcoma

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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) ```