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BIOL 207
Biology of Cancer
Fall 2007
Lecture 4: Metastasis
Reading: Kleinsmith Chap. 3
Outline:
1. .Angiogenesis defined
2. Angiogenesis activators and inhibitors
3. Invasion and metastasis
4. Models of metastasis
a. blood flow patterns
b. “soil and seed”
Lecture:
1. Angiogenesis—sprouting of new blood vessels
 commonly occurs in the developing embryo
 rare in adult except to heal wounds and in females during menstrual cycle
Process of angiogenesis: Fig. 3-1
Undifferentiated cells  converted into endothelial cells  organize into network of
channels  angiogenesis
Angiogenesis is required for tumors to grow > than a few mm.
Fig. 3-2 experiments
(1) Cancer cells provided only a nutrient solution outside the body grow to only 1-2 mm.
(2) Tumor transplanted to different parts of the eye—get different outcomes depending
on the potential for blood vessel growth
Tumors actually release signaling molecules to trigger the growth of new blood vessels.
2. Angiogenesis activators and inhibitors
a. Angiogenesis is triggered by activators, which are + growth factors stimulating the
growth of endothelial cells. Some examples: FGF: fibroblast growth factor, VEGF:
vascular endothelial growth factor.
Activators trigger angiogenesis Fig. 3-5.
b. Also need angiogenesis inhibitors to be removed for angiogenesis to be fully on.
Examples of inhibitors are angiostatin and endostatin, both discovered by Dr. Judah
Folkman.
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Fig. 3-6 Can the inhibitors work as a possible cancer therapy?
A mouse with a large tumor is injected with endostatin caused regression of the
tumor tumor regrew reinject with endostatin and NO MORE TUMOR!
WOW! This sounds like this could be a GREAT CANCER TREATMENT!
Unfortunately, this line of investigation is proceeding slowly.
This approach is called “anti-angiogenic therapy”. At least one anti-cancer drug released
for treatment of colon cancer works in this way. Others are in clinical trials.
The scientist closely associated with angiogenesis inhibitors and anti-angiogenesis
therapies is Dr. Judah Folkman. His lab purified the antiangiogenesis drugs endostatin
and angiostatin from benign tumors (hemangiomas). He showed that these inhibitors
could lead to the regression of a variety of tumor types in mice. However, these drugs
are not really panning out in clinical trials.
3. Invasion and metastasis
Cancers spread through the body by invasion and metastasis.
Invasion—migration and penetration of cancer cells into surrounding tissues.
Metastasis—ability of cancer cells to enter the blood stream and travel to distant
sites to form new tumors.
Fig. 3-8 Steps involved in metastasis
(1) invade surrounding tissues and enter blood vessels
(2) cancer cells travel in bloodstream to distant sites
(3) cancer cells reinvade and grow at a new location
Invasion: Cancer cells show loss of E-cadherin, a cell-cell adhesion protein that holds
endothelial cells together.
Motility: Cancer cells are attracted by signaling molecules, loss of cell adhesion means
they are able to detach from each other.
Proteases: Enzymes that degrade proteins. Cancer cells produce these—they can break
down basement membrane (basal lamina) underlying epithelia or extracellular matrix
surrounding other cell types.
Example: Plasminogen activator
Fig. 3-9 PA can ultimately activate the protease plasmin and other proteases called
MMPs=matrix metalloproteinases.
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Few cancer cells survive the trip through the blood stream. Most lodge first in the
regional lymph nodes where lymphocytes and phagocytic cells recognize them and
mount and immune response.
Ability to metastasize differs among different cancers. A tumor is a heterogeneous
population of cells—not completely genetically identical. Some cells better fit the
“profile” of a metastatic cancer cell.
Fig. 3-10 Selection of melanoma cells with enhanced ability to metastasize to the lung.
Is there any way to predict where metastasis will occur in the body? Why does a
melanoma often metastasize to the lung?
4. Models of metastasis
a. Many tumors follow patterns of blood flow.
b. Soil and seed model
Blood flow: Cancer cells often get stuck in the first capillary bed they encounter.
Fig. 3-11
(1) most body tissues blood flows to the heart via the
vena cava
right atrium
right ventricle
pulmonary artery
lung  capillary bed
pulmonary vein
left atrium
left ventricle
aorta to body
(2) in the gastrointestinal tract, blood flows to
hepatic portal veins
liver  capillary bed
hepatic veins
vena cava
heart
(3) lung cancers metastasize to many different organs
end up dispersed in capillary beds
“Soil and seed” model of metastasis—Metastasis takes place when the seed (a cancer
cell) and the soil (distant organ) are compatible.
2/3 of cancer metastases are explained by blood flow
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for other cancers, some metastasized to organs more often then you would expect, some
less often, based on blood flow.
Prostate cancer bone produces growth factors that stimulate growth of prostate cells.
Tumor progression: Cancer cells change as the tumor progresses from primary
tumor, invasion and metastasis to secondary tumor.
Increased number of genetic changes during tumor progression. Secondary tumor can be
larger and more aggressive than the primary tumor which may go undiagnosed.
Immune system does limit metastasis. However, some tumors carry mutations that help
them evade detection; therefore some tumors are readily spotted by the immune system
and killed, others are not.
Tumor behavior depends on interactions between tumor and host. Fig. 3-13
Specific genes can promote or suppress the ability of cancer cells to metastasize.
Metastasis suppressor gene: CAD1=E-cadherin
Metastasis promoter gene: Twist=regulatory protein that helps determine whether cells
can migrate.
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