Transcript 10. Angiogenesis and Metastasis

10.
การสร้างหลอดเลือดและการแพร่กระจายของมะเร็ง
(Angiogenesis and Metastasis)
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10.1 Tumor Angiogenesis
10.2 Invasion and Metastasis
10. Angiogenesis and Metastasis
10.1 Tumor Angiogenesis
 To survive and grow, all body tissues require a continual supply of oxygen
and nutrients accompanied by the removal of carbon dioxide and other waste
products. ---> Blood vessels
1) Arteries carry blood from the heart to
the rest of the body.
2) Veins carry blood from the body back
toward the heart.
3) Capillaries connect the smallest
arteries and veins. The wall of a
capillary is only a single cell layer
thick.
 Like the cells of any other tissue, tumor
cells require a network of blood vessels to
perform the same tasks.
 The vessels that feed and sustain
tumors are produced by angiogenesis (the
process by which new blood vessels sprout
and grow from pre-existing vessels in the
surrounding normal tissues).
10.1.1 Angiogenesis is prominent in embryos but
relatively infrequent in adults
 Vasculogenesis occurs mainly during embryonic development, in which
undifferentiated cells are converted into endothelial cells that organize
themselves into a network of channels representing the major blood vessels.
 Angiogenesis refers to
the growth and
proliferation of the
endothelial cells that line
the inner surface of
existing blood vessels,
forming buds that sprout
from the vessel wall and
develop into new vessels.
 Angiogenesis continues
to occur after birth when
additional blood vessels
are required.
Kleinsmith LJ. Principles of cancer biology.
Pearson International Edition. Benjamin
Cummings, San Francisco. 2006.
 In adults, the need for new vessels is limited to a few special
situations.
- normal menstrual cycle
- wound healing & tissue repair
 Angiogenesis needs to be precisely regulated in such special situations,
turning on for a short time and then stopping.
 When a need for blood vessels arises, angiogenesis activators increase in
concentration and inhibitors decrease, triggering the proliferation of
endothelial cells and the formation of new vessels.
10.1.2 Angiogenesis is required for tumors to grow
beyond a few millimeters in diameter
 Judah Folkman (1971) suggested that tumors release signaling molecules
that trigger the growth of new blood vessels in the surrounding host tissues
and that these new vessels are required to sustain tumor growth.
 Once the tiny tumors had failed to link up to the blood vessels, the tumors
stopped growing when they reached a diameter of 1-2 mm.
Two experiments showing that tumor growth depends on
angiogenesis.
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006.
 It appeared that tumors must trigger development of a blood supply
before they can grow beyond a tiny mass.
 The process by which cancer cells stimulate the development of a blood
supply is called tumor angiogenesis.
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006.
10.1.3 Angiogenesis is controlled by the balance between
angiogenesis activators and inhibitors
 Cancer cells produce molecules that
diffuse through the tiny pores in the filter
and activate angiogenesis in the
surrounding host tissue.
 More than a dozen proteins, as well as
smaller molecules, can activate
angiogenesis.
Some natural stimulators of angiogenesis
Kleinsmith LJ. Principles of
cancer biology. Pearson
International Edition. Benjamin
Cummings, San Francisco. 2006.
 Vascular endothelial growth factor (VEGF) and fibroblast growth factor
(FGF) appear to be especially important for sustaining tumor growth.
 VEGF and FGF produced by many
kinds of cancer cells (and certain
types of normal cells) trigger
angiogenesis by binding to specific
receptor proteins located on the
surface of endothelial cells.
1) Stimulation of endothelial cell
proliferation.
2) Stimulation of endothelial cell
migration.
3) Secretion of MMPs (Metrix
metalloproteinases) that degrade
components of the extracellular
matrix
Kleinsmith LJ. Principles of cancer biology. Pearson
International Edition. Benjamin Cummings, San
Francisco. 2006.
 For angiogenesis to proceed the angiogenesis stimulators must overcome
the effects of angiogenesis inhibitors that normally restrain the growth of
blood vessels.
 More than a dozen naturally occurring inhibitors of angiogenesis have been
identified, including angiostatin, endostatin, and thrombospondin.
Some natural inhibitors of angiogenesis
Kleinsmith LJ. Principles of
cancer biology. Pearson
International Edition.
Benjamin Cummings, San
Francisco. 2006.
 The balance between the concentration of the inhibitors and the
concentration of activators determines whether a tumor will induce the
growth of new blood vessels.
10.1.4 Inhibitors of angiogenesis can restrain tumor
LJ. Principles of cancer biology. Pearson International
growth and spread Kleinsmith
Edition. Benjamin Cummings, San Francisco. 2006.
Angiogenesisdeficient
mutant mouse
10.2 Invasion and Metastasis
 Once angiogenesis has occurred at the site of a primary tumor, the stage is
set for tumor cells to invade neighboring tissues and spread to distant sites.
 A few kinds of cancers, such as nonmelanoma skin cancers, rarely invade
and metastasize.
 About half of people with other forms of cancers have tumors that have
already begun to spread beyond the site of origin by the time the cancer is
diagnosed.
 A better understanding the mechanisms that allow cancer cells to spread
might be possible to develop improved treatments for cancers.
10.2.1 Spreading of cancer cells by invasion and
metastasis is a complex, multi-step process
 Cancers spread through the body via two distinct mechanisms: invasion
and metastasis.
1) Invasion refers to the direct migration and penetration of cancer cells
into neighboring tissues.
2) Metastasis involves the ability of cancer cells to enter the bloodstream
(or other body fluids) and travel to distant sites.
 The events following
angiogenesis…..
1) Cancer cells invade
surrounding tissues and
penetrate through the wall of
lymphatic and blood vessels,
thereby gaining access to the
bloodstream.
2) Cancer cells are then
transported by the circulatory
system throughout the body.
3) Cancer cells leave the
bloodstream and enter
particular organs, where they
establish new metastatic
tumors.
Kleinsmith LJ. Principles of cancer biology. Pearson
International Edition. Benjamin Cummings, San
Francisco. 2006.
10.2.2 Changes in cell adhesion, motility, and protease
production allow cancer cells to invade surrounding
tissues and vessels
 Several mechanisms make invasive behavior of cancer cells possible.
1) Cell-cell adhesion proteins are often missing or deficient, allowing
cancer cells to separate from the main tumor mass more readily.
----> E-cadherin (normally binds epithelial cells to one another)
2) Activation of cell motility after the loss of cell-cell adhesion.
----> stimulated by signaling molecules (e.g. chemoattractants)
3) Production of protease to degrade the protein barriers that prevent
cancer movement.
----> plasminogen activator (produced by most cancer cells)
Active proteases
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006.
10.2.3 Relatively few cancer cells survive the voyage
through the bloodstream
 Regional lymph nodes are a common site for the initial spread of cancer.
 Cancer cells that initially enter into the lymphatic system eventually arrive
in the bloodstream and circulate throughout the body.
 The bloodstream is an inhospitable place for most cancer cells and only a
tiny number survive the trip to potential sites of metastasis.
10.2.4 The ability to metastasize differs among cancer
cells and tumors
 The cells (heterogeneous
population) in a primary tumor differ
in their ability to metastasize.
 The likelihood that metastasis will
occur appears to be genetically
programmed into the cells of the
primary tumor.
Kleinsmith LJ. Principles of cancer biology. Pearson
International Edition. Benjamin Cummings, San
Francisco. 2006.
10.2.5 Blood-flow patterns often dictate where cancer
cells will metastasize
 The pattern of blood-flow in the
circulatory system determines where
cancer cells are likely to become
lodged.
 Stomach and colon cancers
frequently metastasize to the liver.
 Prostate and breast cancers often
metastasize to bone.
 Many forms of cancer tend to
metastasize to the lungs.
 Lung cancer metastasize to many
different organs.
Kleinsmith LJ. Principles of cancer biology. Pearson
International Edition. Benjamin Cummings, San
Francisco. 2006.
10.2.6 Organ-specific factors play a role in determining
where cancer cells will metastasize
 Paget’s idea (Stephen Paget,1889) is often referred to as the “seed and
soil” hypothesis.
 Metastasis only takes place where the seed ( a cancer cell) and the soil (a
particular organ) are compatible.
 The ability to grow in different locations is affected by interactions
between cancer cells and molecules present in the organs to which they are
delivered.
 Bone cells produce growth factors that stimulate the proliferation of
prostate cancer cells.
10.2.7 Some of the cellular properties involved in invasion
and metastasis arise during tumor progression
 Cancer is a disease whose properties change with time.
 Individual cancer cells often acquire gene mutations and alter the genes
they express, turning on some genes and turning off others.
 Such alterations create a population of cells whose properties, including
the ability to invade and metastasize, gradually change over time.
10.2.8 The immune system can inhibit the process of
metastasis
 Cancer cells are not literally of “foreign” origin, but they often exhibit
molecular changes that allow the immune system to recognize the cells as
being abnormal.
 Animal experiments suggest that in some cases, attack by the immune
system does limit the process of metastasis.
Lung cancer cells
H-2K = cell surface
MHC molecule
Recognized by cytotoxic
T lymphocytes
Kleinsmith LJ. Principles of
cancer biology. Pearson
International Edition.
Benjamin Cummings, San
Francisco. 2006.
10.2.9 Invasion and Metastasis involve a variety of
Tumor-Host interactions
 The behavior of the malignant tumors depends not just on the traits of
cancer cells, but also on interactions between cancer cells and normal cells of
the host.
Kleinsmith LJ. Principles of cancer biology. Pearson
International Edition. Benjamin Cummings, San
Francisco. 2006.
10.2.10 Specific genes promote or suppress the ability of
cancer cells to metastasize
1) Metastasis promoting genes: code for proteins that stimulate events
associated with invasion and metastasis
----> MMP genes
----> Twist gene :- contributes to the lost of adhesive properties
2) Metastasis suppressor genes: code for proteins that inhibit events
associated with invasion and metastasis
----> CAD1 gene:- codes for E-cadherin
----> NM23 gene
----> KiSS1 gene
----> KAI1 gene
----> BRMS1 gene
----> MKK4 gene
Some of these genes code for proteins
involved in cell adhesion and motility.