Cancer Flashcards
definition of tumor
purposeless overgrowth of any cellular component
hyperplasia
physiological proliferative increase in number of cells
dysplasia
change in phenotype (size, shape and organization of tissue
neoplasia
abnormal proliferation, tumor
hypertrophy
increase in cell size
benign
tumors localized and of small size
Ex: warts
WHat delineates the extent of a benign tumor?
fibrous capsule
malignant
grow and divide more rapidly than normal, fail to die at the normal rate, or invade nearby tissue without significant change in proliferation rate
incidence of epithelial origin of cancers
85%
glandular (breast, colon, liver..)
adenoma, adenocarcinoma
adenoma
glandular benign
adenocarcinoma
malignant glandular
covering (skin, lungs, cervix…)
squamous cell papilloma, squamous cell carcinoma
squamous cell papilloma
benign covering
squamous cell carcinoma
malignant covering
epithelial b/m
oma/carcinoma
supporting tissue b/m
oma/sarcoma
bone (osteoblast)
osteoma/osteosarcoma
osteoma
benign bone
osteosarcoma
malignant bone
Striated muscle
rhabdomyoma/rhabdosarcoma
rhabdosarcoma
malignant striated muscle
rhabdomyoma
benign striated muscle
smooth muscle
leiomyoma/leiomyosarcoma
leiomyoma
benign smooth muscle
leiomyosarcoma
malignant smooth muscle
hematopoietic
/leukemia
erythrocytes
erythrocyte leukemia
erythrocyte leukemia
erythrocyte
Lymphocyte
Lymophocyte or lymphocytic
leukemia
bone marrow
myeloma or myeologenous leukemia
no benign version
erythrocytes, lymphocytes, BM
astrocytes
astrocytoma/glioblastoma
astocytoma
astrocytes benign
glioblastoma
astrocyte malignant
melanocytes
mole/melanoma*
mole
benign melanocytes
melanoma
malignant melanocytes
micro-anatomical changes
- lack of differentiation
- abnormal nucleus
- abnormal chromosome
anaplasia
dedifferentiation or lack of differentiation
pleomorphic
variation in size or shape
FISH
paints chromosome
Behaviorial characteristics of cancer cells
- ability to proliferate indefinitely
- resistance to apoptosis
- anchorage-independent growth
- loss of contact-inhibition
- decreased requirement for growth factors
- increased metabolism
- form tumor in lab animals
- loss of cell-cell adhesion
- invasion and metastasis
- escape from immune surveillance
PET scan
can see metabolism
monoclonal theory of cancer origin
arise from a single cell of origin
any cell could create tumor
cancer stem cell theory of cancer origin
relies on the fact that a lot of tumors are heterogenous (vary by phenotype and functions)
ONLY CSC CAN CREATE TUMOR
both origin theories
clonal evolution regulated by cancer stem cells
tumor cells and stem cells
share many similarities self-renewal differentiation active telomerase expression anti-apoptotic ability to migrate
evidence of monoclonality
X-chromosome inactivation patterns
Use of starch gel electrophorsis to resolve the two forms of G6PD showed that all of the cancer cells in a tumor arising in a G6PD heterozygous patient express one or the other
additional evidence of monoclonality
unusual translocation involves exchange of segments between two separate (nonhomologous) chromosomes - all of the cancer cells carry the identical rare translocation - > monoclonality
differences of incidence by area of the world
suggests strong environment involvement
What causes cancer?
- chemical agents
- radiation (UV, ionizing)
- infectious agents (virus)
- heredity
carcinogens vs mutagens
carcinogens are mutagens
test mutagens
Ames test
Ames test for gauging mutagenicity
liver is homogenized - releasing the enzymes that can metabolically activate a chemical to mutagenic form
- mixed with test compound
- add to Salmonella bacteria unable to grow w/o histidine in culture
- count colonies
Rous’s protocol for inducing sarcomas in chickens
Removed sarcoma from breast muscle of chicken
- pass through fine pore filter
- filtrate into wing web of a young chicken
- sarcoma*
Therefore, VIRUS.
RSV
transformation
conversion of a normal cell into a tumor cell could be accomplished with RSV
three major types of viral proteins
env - glycoprotein spike (adsorb to cell surface)
gag - protein coat of core proteins
pol - specify reverse transcriptase molecules
temperature sensitive mutant and the maintance of transformation by RSV
- infected at permissive temp (transformed)
- shifted to non permissive (normal)
- back to permissive temp (transformed again)
Thus, temp sens viral protein must be active to transform cell.
viruses containing DNA molecules
are also able to induce cancer
Important discoveries of viruses and cancer
- transformed cells integrate viral genome
- Some viral genomes have genes that can transform cells (these have no function in viral replication)
- transforming genes have counterparts in host cells
- often viral oncogenes are mutated and hyperactive
- cellular proto-oncogenes can also be activated by insertion of slowly transforming retrovirus lacking oncogenes (insertional mutagenesis)
nude mice in testing tumorigenicity
- lack thymus/immunocompromised; receptive to engrafted cells
- hairless - easy to monitor closely the progress of tumor formation
oncogenes
gene with the potential to cause cancer
gain of function drives toward cancer
proto-oncogene
gene that can become an oncogene if mutated or expressed at high levels
insertional mutagenesis
cellular proto-oncogenes can also be activated by insertion of slowly transforming retrovirus lacking oncogenes
tumor supressor gene
loss of function
two categories of cancer-critical mutations
dominant (oncogene)/recessive (tumor suppressor gene)
conversion of protooncogene to oncogene
- deletion or point mutation - hyperactive protein made in normal amounts
- regulatory mutation - normal protein overproduced
- gene amplification - normal protein overproduced
- chromosome rearrangement
a. normal protein overproduced
b. hyperactive protein
Screening of oncogenes
transfection
- DNA extracted from cancer cells
- DNA uptake by cells
- if has oncogene, result in tumor formation
Cloning of transfected oncogenes
Southern blotting
Alu sequence probe, ones that were transfected successfully were oncogenes in the mouse
-genomic library and DNA clone could be identified
cloned proto-oncogene
no transfection
cloned oncogene
transfection
localization of an oncogene-activating mutation - point mutation - Ras
endonuclease with a protooncogene
until you get a fragment that transfects the proto-oncogene
activating mutant of Ras…
fails to hydrolyze GTP
Sos
Ras GEF
Grb2
bridging protein of Sos to ligand-activated growth factor receptors due to two SH3 domains
bind to proline rich domains of Sos
Two bridging proteins of Sos
Grb2 and Shc
Ras/Raf/MAP kinase pathway
Ras->Raf->MEK->ERK (MAPK)
- Fos and Jun Tx factors, associate with one another to form AP-1, found in hyperactive cancer cells
translocation
fuse a region from one chromosome with another region from a second, unrelated chromosome
ongenic activation of myc
- gene amplification
- insertional mutagenesis (WT mys locus, but under foreign promoter
- chromosomal translocation
myc driven under
IgH promoter - Burkitt’s lymphoma
truncated growth factor receptor causing
deregulated firing
Ex: truncated EGF receptor in breast
structural changes in protein
can also lead to oncogene activation
conceptualized existence of tumor suppressor genes by
cell fusion
- tumorigenic - dominant
- not - recessive
Rb (retino blastoma)
first identified tumor suppressor gene
genetic mech that cause Rb
hereditory - every one has one missing
nonhereditory - all cells contain functional…both are lost or inactivated
elimination of WT Rb gene copies
LOH
loss of heterozygosity
from mitotic recombination/crossing over
p53
tumor suppressor
suppresses Ras induced transformation of fibroblasts
mutant p53
has dominant negative function
accumulation of p53
cell-cycle arrast, DNA repair, block angiogenesis, apoptosis
p53 controlled by
Mdm2 - causes p53 proteolysis
p53 targets
p21 (cell cycle inhibitor)
PUMA (pro-apoptotic)
ARF
binds to Mdm2 and blocks p53 degradation
loss of p53 function
excessive proliferation, inhibition of apoptosis and DNA damage repair
loss of function of tumor suppressor genes caused by
genetic and epigenetic factors
methylation!
How do you search for tumor suppressor genes?
LOH analyses by RFLP (restriction fragment length polymorphism)
rationale: chromosomal region flanking tumor-suppressor gene is likely to undergo LOH
Tumor Progression
growth and dissemination
new blood vessel generation…
is critical for primary tumor growth
hypoxic cells
die
distance from blood vessel
100-200 mm
hypoxia triggers
angiogenesis
angiogenesis aids…
survival of tumor cells
metastatic dissemination requires
new blood vessel generation
leaky tumor vasculature promotes
intravasation
metastatic colonization requires
angiogenesis
4 ways to recruit blood vessels to tumors
- sprouting angiogenesis (predominant)
- vasculogenesis
- vascular mimicry
- Csc differentiation
sprouting angiogenesis
new vessel generation from pre-existing vessels
VEGF signaling promotes
- junctional disruption
- proliferation
- survival
- migration
- recruitment of EPCs
VEGF upregulation
in cancer
major triggers of VEGF
hypoxia, oncogenic signaling
H1F1-alpha
regulated by oxygen
major oncogenic signaling
PI3K, Ras PI3K mutation Activated EGFR AKT mutation PTEN loss RAS activation
multicellular interactions in the tumor microenvironment
promote tumor angiogenesis
key players in tumor angiogenesis
tumor cells, EC, matrix remodeling, secretion of pro-angiogenic factors, myeloid cells (macrophages ECM deg)
block VEGF signaling
block progenitor cell recruitment
vascular mimicry
channel formation
CSC differentiation into
Endothelial cells
epithelial to mesenchymal transition
promotes tumor invasion
E-cad staining (loss of E-cadherin)
reciprocal stimulation
promotes tumor invasion/intravasation
macrophages and fibroblasts secrete
mmps
Treatments
surgery
radiation
chemotherapy
adjuvants
chemotherapy treatments
- antimetabolite (analogs)
- microtuble stabilizing (taxol)
- DNA cross-linking agents (cisplatin)
- antibiotics (doxorubicin
- hormone therapy (tamoxifen)
adjuvent
anti-angiogenic drug (VEGF antibody)
growth-factor receptor blocker (EGFR antibody)
Problems with therapy
- side effects
- delivery issues
- redundancy of mol players and pathways (single line adjuvant therapy is not often sufficient)
- increased drug resistance (over expression of transporter proteins)
- resistance offered by cancer stem cell
Tumor vessels are abnormal
- leaky
- tortuous
- heterogeneous
- poor pericyte coverage
- thin basement membrane
