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• Cancer – What is it?
1.
What is the difference between a benign tumor and a malignant tumor?
2.
What is the difference between a sarcoma and a carcinoma?
3.
Cancer forms most commonly in what tissues?
4.
What are some common mechanisms thought to “cause’ cancer?
5.
Are some types of cancer more “curable” than others?
True/False?
• Most cancers are derived
from a single abnormal cell
• Most cancers develop due
to a single mutation in a
cell’s DNA
Name at least three key
properties that make cells
capable of cancerous
growth.
• Tumors are generally traced to a
single cell that has undergone a
heritable change that gives it the
ability to outgrow its neighbors.
• Detectable at about a billion cells
or more
• Due to a genetic change (mutation)
or an epigenetic change?
Genes from maternal or paternal side,
can influence the production or inhibition
of other genes.
Normal incidence of mutation:
10-6 mutations per gene per cell
division
Lifetime accumulation of
mutations:
1010 mutations in each gene
So Why Isn’t Cancer More
Common?
Tumors may progressively
accumulate mutations
They may grow sporadically,
increasing in size when a
particular advantageous mutation
gives a cell a selective advantage
over its neighbors
Tumors may also regress if
advantageous mutations do not
occur and the existing cells
cannot survive in the environment
they create
What characteristics give cancer cells
an advantage?
• Genetic instability
• Defective control of cell death or cell
differentiation
• Loss of proliferation controls
• Ability to survive in an alien
environment
Proto-oncogenes
Tumor suppressor
genes
How would you find the identity of an oncogene?
• Find a convenient “test” cell line that already has some cancer-like
characteristics
• Extract DNA from tumor cells; fragment it; transfect test cells
Examples of Cancer-Critical
Genes:
Ras (oncogene)
Myc (oncogene)
Find at least two abnormalities in this human karyotype.
Pairs of chromosomes should be the same colors
What characteristics give cancer cells
an advantage?
• Genetic instability
• Defective control of cell death or cell
differentiation
• Loss of proliferation controls
• Ability to survive in an alien
environment
Myeloid leukemia
What characteristics give cancer cells
an advantage?
• Genetic instability
• Defective control of cell death or cell
differentiation
• Loss of proliferation controls
• Ability to survive in an alien
environment
Replicative cell senescence
What characteristics give cancer cells
an advantage?
• Genetic instability
• Defective control of cell death or cell
differentiation
• Loss of proliferation controls
• Ability to survive in an alien
environment
Preferential metastatic sites
Primary tumour
Common distant site (s)
Breast’ adenocarcinoma
Bone, brain, adrenal
Prostate adenocarcinoma
Bone
Lung small cell carcinoma
Bone, brain, liver
Skin cutaneous melanoma
Brain, liver, Bowel
Thyroid adenocarcinoma
Bone
Kidney clear cell carcinoma
Bone, liver, thyroid
Testis carcinoma
Liver
Bladder carcinoma
Brain
Neuroblastoma
Liver, adrenal
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Colon adenocarcinoma in lung tissue.
Glandular structure and cells very
similar to colon. Necrosis internally.
Reason for organ selectivity
Mechanistic theory: determined by the pattern
of blood flow.
“Seed and soil” theory: the provision of a fertile
environment in which compatible tumor
cells could grow
Determining factors
• Appropriate growth factors or extracellular
matrix environment
• Compatible adhesion sites on the endothelial
lumenal surface
• Selective chemotaxis at which the organ
producing some soluble attraction factors to
the tumor cells
5 major steps in metastasis
1.
2.
3.
4.
5.
Invasion and infiltration of surrounding normal host tissue
with penetration of small lymphatic or vascular channels;
Release of neoplastic cells, either or single cells or small
clumps, into the circulation;
Survival in the circulation;
Arrest in the capillary beds of distant organs;
Penetration of the lymphatic or blood vessel walls followed
by growth of the disseminated tumor cells
Tumor invasion
1. Translocation of cells across extracellular matrix
barriers
2. Lysis of matrix proteins by specific proteinases
a)
b)
MMP2 and MMP9, which cleave type IV collagen the major constituent of
basement membrane, are believed to be of special importance
Serine protease involved in ECM degradation are plasmin, plasminogen
activators and cathepsin G.
3. Cell migration
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Interaction between tumour cells and the
surrounding connective tissue
1.
2.
Integrin: cell-matrix
adhesion
• Integrin can affect the
transcription of MMP genes
E-cadherin/catenin
adhesion complex: cellcell adhesion
• Reduce expression of Ecadherin and catenin
increase the invasiveness
of tumor cells
p120 catenin
Cell migration
1.
2.
Small Rho GTPase family
Motility promoting factors
Small Rho GTPase
Stimuli
Cdc42
Rac1
GTP
GTP
Pak1
MLC Kinase
LIM kinase
Stress fibers
MLC Phosphorylation Cofilin
Contraction
Filopodia
Actin polymerisation
Detachment
Lamellipodia
Rho GTPase is required for the transition
of invasive phenotype
How Can We Mimic and Study Metastasis?
Cancers are formed viaTumor Initiators ,Tumor Promoters,
or Viruses
Tumor initiators – damage DNA
•Aflatoxin
•Vinyl chloride
•Benzene
•Arsenic
•Asbestos
Tumor promoters – not mutagenic themselves; promote growth and
differentiation without affecting DNA. They do this via
inflammatory response – causes secretion of growth factors and
proteases in the local environment. Can regress if the promoter is
removed (example: warts).
• palytoxin
•thapsigargin
Viruses and Cancer
Major Treatments for Tumors (benign and metastatic)
Surgery
Chemotherapy
Radiation
New Treatments
Drugs
http://www.chemocare.com/bio/
Retinoic Acid –
•
•
•
•
derivative of vitamin A;
used to control cell growth and differentiation;
binds to a class of nuclear receptors;
used in cancers such as skin cancers, cutaneous T-cell lymphoma, acute
promyelocytic leukemia, lung cancer, breast cancer, ovarian cancer, bladder cancer,
kidney cancer, and head and neck cancers.
Adriamycin/Doxorubicin
• Cancers treated with adriamycin include: bladder, breast, head and neck,
leukemia (some types), liver, lung, lymphomas, mesothelioma, multiple
myeloma, neuroblastoma, ovary, pancreas, prostate, sarcomas, stomach,
testis (germ cell), thyroid, uterus
• Targets fast dividing cells of all types; antibiotic nature of these drugs
destroys cells
Radiation (external or internal)
Brachytherapy