Cancer exam 1

Norm Behavior for a cell

Norm Behavior for a cell

Proliferate, differentiate, reside in specific locations, die or undergo senescence

Hallmarks of cancer

Growth signal self sufficiency, insensitivity to anti-growth signals, evading apoptosis, limitless replication, sustained angiogenesis, invasion and metastasis

Homologs

Genes within a species that are similar to each other

Orthologs

Same gene in different species

SKY and mFISH

Allow chromosomes to be distinguished by color in karyotypes

Gene expression microarray

Shows which genes are up/down regulated

Ways to regulate gene expression

Transcription factors, post-translational modifications, methylation of CpG islands, mRNA splicing, miRNAs

Transcription Factors

Bind to short DNA sequences and recruit RNA pol II

Nucleosomes

DNA wrapped around histones

Methylation

Silences genes, epigenetic, can happen to CpG islands or histone proteins, alters chromatin structure

Benign

A tumor that hasn’t broken through the basal membrane or metastasized

Malignant

A tumor that has broken through basement membrane or metastasized

Metastases

Tumors that have moved from their original tissues to other sites

Ways to classify cancers

Embryonic origin, cell type, behavior, mutations or gene expression

Carcinoma

Epithelial tumor, 80% of cancer deaths

Adenocarcinoma

From secretory epithelial cells

Sarcoma

From mesenchymal tissue such as fibroblasts, adipocyes, osteoblasts, myocetes

Hematopoietic cancers

Cancers from blood forming tissue

Leukemia

Cancers of circulating cells

Lymphomas

Cancers of B and T lymphocytes

Neuroectodermal tumors

Gliomas, glioblastomas, neuroblastomas, schwanommas, medulloblastomas, from nervous system

Melanomas

From melanocytes

Small cell lung carcinoma

Lung cancer with neurosecretory properties

Teratomas

Tumors that retain pluripotency, genetic manipulation of germ line cells

Basal Lamina

Aka basement membrane, divides mesenchymal and epithelial tissues, made of extracellular matrix

Mesenchymal tissue

Connective tissue beneath epithelial tissue, contains fibroblasts, fibers, capillaries, etc.

Squamous cell carcinoma

tumor of flat epithelial cells, like skin

Hyperplasia

More than usual number of cells with normal morphology

Metaplasia

Cell layer is displaced by cells of a type that isn’t usually found there, with normal morphology

Dysplasia

Abnormal morphology

Polyp

Aka adenomas, dysplasia grows large but doesn’t break basement membrane

Hyperplasia, metaplasia, dysplasia, polyp, metastatic

Basic progression of tumors

Stage 0

Carcinoma in situ

Stages 1-3

Large tumor size, spread beyond organ of origin to nearby nodes/ tissues

Stage 4

Cancer has spread to distant tissues

Monoclonal

Tumor arising from a single cell

Polyclonal

Tumor arising from multiple different cell lines

Warburg Effect

Cancer cells need a lot of glucose, so they rely on glycolysis. Switch from PKM1 to PKM2

FDG-PET scans

Used to detect tumors by scanning for increased glucose uptake

Ames test

Uses deficient bacteria to test for mutagens, only those who mutate survive

Epidemiology

Study of the incidence and distribution of a disease

Foci

transformed cells form clusters in culture

Nude mice

Good model organisms for studying cancer, have been genetically engineered to be bald

Permissive temperature

Temperature at which virus proteins are active

Retrovirus

Genes are encoded by RNA, not DNA. RSV

Reverse transcriptase

Makes a dna copy of the rna

SRC

A gene found in both viruses and cells as different types, important for transforming cells, a kinase phosphorylating tyrosine

Oncogene

A gene that causes cancer

Proto-oncogene

A gene whose mutation turns it into an oncogene

HPV

Human papilloma virus, a DNA virus with more than 150 types, main cause of cervical cancers and genital warts. Has genes E6-E7 that transform the host

E6

An early gene of hpv that leads to ubiquitination and degradation of p53

E7

An early gene of hpv that binds Rob, leading to production of cell cycle proteins

Transfection focus assay

DNA from chemically transformed mouse cells are transfected into normal cells in culture to form a focus, then injected into mice to monitor tumors. Used to measure the oncogenic potential of a gene

How Proto-oncogenes become oncogenes

Amplification, translocation, point mutations

ErbB

An RTK in the EGFR family commonly overexpressed in lung and breast cancers, v-erbB is truncated

Kaplan-Meier plot

disease free survival after treatment

Rasv12

an oncogenic version of Ras with a mutation at valine 12 which slows rate of gtp hydrolysis, most common ras mutation

Ras

a small g protein, important for cell proliferation and movement signaling

GAP

induces gtp hydrolysis to gdp

GEF

exchanges gdp for gtp

BCR-ABL

fusion of Abl (tyrosine kinase) and BCR (has SH2 domain) to make a constitutively active protein

Burkitt’s lymphoma

three separate translocations where myc transcription is put under control of promoter for immunoglobulin protein, connected with epstein-barr virus which increases number of B lymphocytes

Tyrosine Kinases

a type of kinase often mutated in cancers, can be receptor (EGFR) or non-receptor (src, abl)

growth factors

allow communication between cells to govern differentiation, proliferation, movement, and cell death

PDGF

platelet derived growth factor, binds to receptors on surface of fibroblasts, activating proliferation and movement into wounds

SH1 domain

src homology domain, tyrosine kinase domain, found in all RTKs

EGFR

RTK, binds to EGF which causes it to dimerize and transphosphorylate

integrins

two subunits, transmembrane receptor protein, link ECM to cytoskeleton at focal adhesions

stress fibers

actin, pull on adhesion sites to mediate cell movement

frizzled

receptor for wnts

Patched

receptor for hedgehog

notch

receptor for delta, truncated notch is constitutively active

GSK3beta

kinase in a complex with axin and Apc, phosphorylates b-catenin for degradation

smoothened

transmembrane protein inhibited by patched

PTEN

reduces activation of AKT by opposing PI3K, tumor supressor

IkappaB

what inhibits NFkappaB

Delta

binds to Notch to initiate signaling

JAKS

tyrosine kinases associated with cytokine receptors

Grb2

adaptor protein with SH2 and SH3 domains, can bridge RTKs to Ras with Shc and Sos

STATS

transcription factors that associate with JAKS, translocate to nucleus, dimerize through their SH2 domains

SMADs

transcription factors that associate with TGFbeta receptors, 2/3/4 translocate to nucleus

SH2 domain

domain that binds phosphotyrosine, especially phosphotyrosine on RTKs

PH domain

domain that binds PI(3,4,5)P3

SH3

Domain that binds proline-rich regions

SH1

domain with active tyrosine kinase actvity

14-3-3 domain

binds phophoserine

B-catenin

protein that translocates to nucleus downsteam of wnt,

MAPK

translocates to nucleus downstream of RTK signaling

Gli

translocates to nucleus downstream of hedgehog signaling. smoothened inhibition clips gli, and gli fragments inhibit transcription.

immediate early genes

usually transcription factors, transcribed with existing transcription factors, first 30 minutes, occurs in presence of cycloheximide, cytoskeletal rearrangements

delayed genes

transcribed in response to IEGs

PTB domain

other domain that binds phosphotyrosine

Bromo

domain binding acetylated lysine

Raf pathway

Ras → Raf (MAPKKK) → MEK → ERK → proliferation

PI3K pathway

Ras → PI3K → PIP3 →Akt or Rho GEFs → proliferation (AKT) or actin stess fibers (Rho)

Rho

small g protein, actin stress fibers

Ral pathway

Ras →Ral GEFs →RalA/B →Cdc42(filopodia) or Rac (lamellipodia), could also end in vesicle fusion

Rac

promotes lamellipodia formation

Cdc42

promotes filopodia formation

Cyclin D

controls entry into cell cycle from R point of G1, controlled by extracellular signals