PDF

Robert A.
Weinberg
The Biology of Cancer

First Edition
Chapter 14:
Moving Out:
Invasion and Metastasis
Copyright © Garland Science 2007
CT-PET fusion
image of
a lymphoma
patient
Figure 14.1 The Biology of Cancer (© Garland Science 2007)

Pancreas of Rip-Tag transgenic mouse (transgene of
SV40 large T and small T antigens)
The Rip-Tag model of islet cell tumor progression
Metastatic islet cell tumor in a lymphatic channels
Endothelial cells
Figure 14.2a The Biology of Cancer (© Garland Science 2007)

Breast cancer cells in lymph node
Figure 14.2b The Biology of Cancer (© Garland Science 2007)
Metastatic cancer cells in bone marrow (Wright-Giemsa stain
Figure 14.2c The Biology of Cancer (© Garland Science 2007)

Section 1.
Travel of cancer cells from a

primary tumor to a site of potential
metastasis depends on a series of
complex biological steps

The structure of
basement membrane
(specialized ECM)
Hemidesmosome is
composed of integrin
and laminin
The structure of basement

membrane
Extra-cellular Matrix
(ECM) protein

The invasion metastasis cascade: six steps are involved
Patterns of Invasion
Lobular
carcinoma
of breast

Red: E-cadherin, green: beta-1-integrin, blue: matrix
Melanoma cells
Squamous cell carcinoma of cervix


Intra-vital microscopy

Intravital fluorescence microscopy
Green: plasma
Red: RBC
Confocal microscopy
Green: rat fibrosarcoma cell
Red: LDL of the arteriole
5 days after injection of single cells injection into mouse vein

Diapedesis
Extravasation
Cancer cell push aside the
endothelial cells, reach
basement membrane
Resolving of the thrombus
Section 2.
Colonization represents the most
complex and challenging step of
the invasion-metastasis cascade
Micro-metastasis in bone marrow: colon cancer
(anti-cytokeratin antibody stain)
Micro-metastasis in bone marrow: breast cancer

Two clusters of lung adenocarcinoma in the lymph node
Genetic heterogeneity of micrometastasis and the evolution of

colonizing ability
Figure 14.11a, b The Biology of Cancer (© Garland Science 2007)

Persistence of solitary dormant (冬眠) tumor cells many

weeks after introduction into the liver
Following isolation and in vitro culturing, the descendants

of many of these cells were tumorigenic

Section 3.
The epithelial-mesenchymal
transition and associated loss of E-
cadherin expression enable
carcinoma cells to become invasive
Embryogenesis and the epithelial-mesenchymal transition (EMT)
Sea urchin embryo

Table 14.1 The Biology of Cancer (© Garland Science 2007)

The program of wound healing
EMT was provoked by a 3-day-long exposure to MMP-3 , which

could initiate EMT through its ability to degrade E-cadherin.
red: cytokeratin, green: vimentin

Individual cells may spontaneously have EMT,
suggesting the plasticity of these cells.
Green: actin
Red: cytokeratin
The serial changes of a mono-layer of breast epithelial cells

after a patch of cells were removed.

EMT at the invasive edge of a malignant tumor
Immunohistochemical stain for E-cadherin

Immunohistochemical stain for β-catenin


Immunofluorescence stain of Keratinocytes

Yellow: E-cadherin, red: actin
Figure 13.12d The Biology of Cancer (© Garland Science 2007)


Table 7.1 part 1 of 2 The Biology of Cancer (© Garland Science 2007)

Table 7.1 part 2 of 2 The Biology of Cancer (© Garland Science 2007)

The EMT can be induced by several transcriptional factors
Example: Twist on canine kidney cells

Section 4.
The epithelial-mesenchymal
transition is often induced by
stromal signals
Reversibility of EMT:
Release of degradative enzymes, such as MMPs, is noted in EMT.
EMT may be triggered by the signals from the tumor associated stroma
Red: CK18
Green: basement membrane

The reversibility of EMT explains the peculiarity of many

metastasis: they are similar to the primary tumor

Manifestation of EMT at the interface between tumor
epithelium and stroma
Laminin-2γ

Vimentin

Abudant evidence indicates that TGF-β is an important agent
for conveying these stromal signals
Control of the EMT by TGF-β and its effect on tumorigenic cells


Figure 14.20e The Biology of Cancer (© Garland Science 2007)
TNF-α and TGF-β contribute to active NF-kB signaling
NF-kB signaling was necessary for EMT in the EpRas cell line

The effect of stromal macrophages on the invasive and metastatic
behavior of cancer cells
Transgenic mice model
TAM(+) TAM (-)
Colony stimulating factor -1 (CSF-1) for recruit tumor associated macrophages

(TAM)
Colony stimulating factor -1 (CSF-1) for recruit tumor

associated macrophages (TAM)

Metastasis in the lung increase with age in the CSF-1(+) mice


Since macrophages are often found in close to microvessels,
the stimulation by tumor associated macrophages (TAM) may
also contribute to cancer cell intravasation
Cell scattering and invasive behavior induced by

hepatocyte growth factor (HGF) or SF
HGF is another ligand of stromal origin, which is also capable of

inducing EMT in the epithelial cells trough the effect of Met protein
(HGF receptor)
Signals that triggered EMT
Section 5.
EMTs are programmed by
transcription factors that orchestrate
key steps of embryogenesis
Embryonic transcriptional factors programing EMT


Figure 14.26e The Biology of Cancer (© Garland Science 2007)

Figure 14.26f The Biology of Cancer (© Garland Science 2007)
Slug
transcription
factor in
wound
healing

Expression of EMT-inducing embryonic transcription factors in human tumors
Slug suppress E-cadherin transcription


Embryonic transcription factors and tumor progression

Embryonic transcription factors and tumor progression
Similarities
between EMT
signaling
during
embryogenesis
and tumor
progression

Mammary carcinoma arising from transgenic MMTV-polyoma T mice
Matrix metalloproteinases (MMPs) produced by tumor associated cells, would

generate a halo of proteolysis (right figure)
The ability of tumor cells to degrade collagen IV fibers

trough interaction with fibroblasts
Red: fibroblast
Green: degraded
collagen IV

Macrophages are important source of MMPs
Elevated MMP-2
imparted increased
invasiveness to the
breast cancer cells
Section 6.
Extracellular proteases play key
roles in invasiveness
Tumor-
associated
macrophages

VEGF expression in tumor cells VEGF expression in TAM

TAM with expression of MMP-9, a key enzyme in
angiogenesis and invasiveness.
Contribution of macrophages to tumorigenesis

Podosomes are small, focal protrusions from the cell surface, that
are used to degrade the extracellular matrix (ECM) of immediate
vicinity. In cancer cells, they can also be called as invadosomes
Red: actin, green: ECM protein
Ectopic expression of MMP-3 and mammary tumor progression

Activation of extracellular proteins: MMPs and TGF-β by uPA and uPAR
uPA: urokinase
plasminogen
activator
Section 7.
Small Ras-like GTPases control
cellular processes including
adhesion,cell shape,and cell motility
Lamellipodia of rat liver cells

Lamellipodia of a fibroblast
Red: actin Green:Ena protein
Fish keratinocytes with prominent lamellipodia. EM demonstrate

densely woven network of actin filaments to extend the
lamellipodia in the direction of movement.

The addition of heregulin induce the development of
lamellipodia that faces all directions
Breast cancer cells Green: actin
Filopodia

The leading edges of lamellipodia are ofteninterspersed with filopodia
The actin fibers within a filopodium

Effects of Rho-like proteins on the actin cytoskeleton and cell adhesion


The circuitry
mediating EGF-
induced cell
motility

Influence of RhoC on metastasis
Section 8.
Metastasizing cells can use
lymphatic vessels to disperse from
the primary tumor
Draining lymph nodes of the mammary glands
Detection of sentinal lymph node by injection of a blue dye


Section 9.
A variety of factors govern the
organ sites in which disseminated
cancer cells form metastases
Primary tumors and their metastatic tropisms

Section 10.
Metastasis to bone requires the
subversion of osteoblasts and
osteoclasts
Bone degradation by osteoclasts
An osteoclast has excavated a shallow pit, which

revealed the complex meshwork of the bone matrix.

Osteolytic lesion by tumor metastasis (scanning EM)

The physiologic balance between bone formation and resorption
osteoprotegerin
The vicious cycle of osteolytic metastasis
The bone matrix

is a rich source of
mitogenic and
trophic factors
Parathyroid hormone
related peptides

MDA-MB-231is a breast cancer cell line usually produce osteolytic metastasis.
TGF-β stimulates osteolytic activity by forcing the breast cancer cells to

release PTHrP, which activate osteoblasts, then--- osteoclasts.
Section 11.
Metastasis suppressor genes
contribute to regulating the
metastatic phenotype
Section 12.
Occult micrometastases threaten
the long-term survival of cancer
patients

Use of expression array to predic disease progression

Gene similarity between primary tumors and derived metastasis

Some expressed genes within tumor cells facilitate
specific types of metastasis
The End

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Robert A.

The Biology of Cancer

Copyright © Garland Science 2007

Figure 14.1 The Biology of Cancer (© Garland Science 2007)

The Rip-Tag model of islet cell tumor progression

Figure 13.37 The Biology of Cancer (© Garland Science 2007)

Metastatic islet cell tumor in a lymphatic channels

Figure 14.2a The Biology of Cancer (© Garland Science 2007)

Figure 14.2b The Biology of Cancer (© Garland Science 2007)

Metastatic cancer cells in bone marrow (Wright-Giemsa stain

Figure 14.2c The Biology of Cancer (© Garland Science 2007)

Travel of cancer cells from a

Figure 14.3 The Biology of Cancer (© Garland Science 2007)

Figure 13.5a The Biology of Cancer (© Garland Science 2007)

The structure of basement

Figure 13.5b The Biology of Cancer (© Garland Science 2007)

Figure 14.4 The Biology of Cancer (© Garland Science 2007)

Figure 14.5a The Biology of Cancer (© Garland Science 2007)

Figure 14.5b The Biology of Cancer (© Garland Science 2007)

Squamous cell carcinoma of cervix

Figure 13.39a The Biology of Cancer (© Garland Science 2007)

Figure 14.7a The Biology of Cancer (© Garland Science 2007)

Figure 14.7b The Biology of Cancer (© Garland Science 2007)

5 days after injection of single cells injection into mouse vein

Resolving of the thrombus

Figure 14.9 The Biology of Cancer (© Garland Science 2007)

Figure 14.10a The Biology of Cancer (© Garland Science 2007)

Micro-metastasis in bone marrow: breast cancer

Figure 14.10b The Biology of Cancer (© Garland Science 2007)

Figure 14.10c The Biology of Cancer (© Garland Science 2007)

Genetic heterogeneity of micrometastasis and the evolution of

Figure 14.11a, b The Biology of Cancer (© Garland Science 2007)

Persistence of solitary dormant (冬眠) tumor cells many

Following isolation and in vitro culturing, the descendants

Figure 14.12 The Biology of Cancer (© Garland Science 2007)

Embryogenesis and the epithelial-mesenchymal transition (EMT)

Sea urchin embryo

Table 14.1 The Biology of Cancer (© Garland Science 2007)

Figure 13.14 The Biology of Cancer (© Garland Science 2007)

EMT was provoked by a 3-day-long exposure to MMP-3 , which

red: cytokeratin, green: vimentin

Figure 13.13a The Biology of Cancer (© Garland Science 2007)

Figure 13.13b The Biology of Cancer (© Garland Science 2007)

The serial changes of a mono-layer of breast epithelial cells

Figure 13.13c The Biology of Cancer (© Garland Science 2007)

EMT at the invasive edge of a malignant tumor

Immunohistochemical stain for E-cadherin

Figure 14.14a The Biology of Cancer (© Garland Science 2007)

Figure 14.14b The Biology of Cancer (© Garland Science 2007)

Figure 14.14c The Biology of Cancer (© Garland Science 2007)

Figure 13.12b The Biology of Cancer (© Garland Science 2007)

Immunofluorescence stain of Keratinocytes

Figure 13.12d The Biology of Cancer (© Garland Science 2007)

Figure 14.16a The Biology of Cancer (© Garland Science 2007)

Table 7.1 part 1 of 2 The Biology of Cancer (© Garland Science 2007)

Table 7.2 The Biology of Cancer (© Garland Science 2007)

Figure 14.15a The Biology of Cancer (© Garland Science 2007)

Figure 14.15b The Biology of Cancer (© Garland Science 2007)

Figure 14.17a The Biology of Cancer (© Garland Science 2007)

The reversibility of EMT explains the peculiarity of many

Figure 14.18 The Biology of Cancer (© Garland Science 2007)

Figure 14.19a The Biology of Cancer (© Garland Science 2007)

Figure 14.19b The Biology of Cancer (© Garland Science 2007)