capitulo de biolgia del cancer

8/22/2019 capitulo de biolgia del cancer

http://slidepdf.com/reader/full/capitulo-de-biolgia-del-cancer 1/73

The Biology of Cancer First Edition

Chapter 14:

Moving Out:

Invasion and Metastasis

Copyright © Garland Science 2007

Robert A. Weinberg

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

CT-PET fusion

image of

a lymphoma

patient




Pancreas of Rip-Tag transgenic mouse (transgene of

SV40 large T and small T antigens)

The Rip-Tag model of islet cell tumor progression

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

Endothelial cells

Metastatic islet cell tumor in a lymphatic channels



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

Breast cancer cells in lymph node

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

Metastatic cancer cells in bone marrow (Wright-Giemsa stain



Section 1.

Travel of cancer cells from aprimary tumor to a site of potentialmetastasis depends on a series ofcomplex 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


Lobular

carcinoma

of breast

Patterns of Invasion




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




Cancer cell push aside the

endothelial cells, reach

basement membrane

Diapedesis

Resolving of the thrombus

Extravasation

Section 2.

Colonization represents the mostcomplex and challenging step ofthe 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

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

Genetic heterogeneity of micrometastasis and the evolution of

colonizing ability





Persistence of solitary dormant (冬眠) tumor cells many

weeks after introduction into the liver

Following isolation and in vitro culturing, the descendantsof many of these cells were tumorigenic



Section 3.

The epithelial-mesenchymaltransition and associated loss of E-cadherin expression enablecarcinoma 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


red: cytokeratin, green: vimentin

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

could initiate EMT through its ability to degrade E-cadherin.




Green: actin

Red: cytokeratin

Individual cells may spontaneously have EMT,

suggesting the plasticity of these cells.


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

after a patch of cells were removed.





Immunohistochemical stain for E-cadherin

EMT at the invasive edge of a malignant tumor




Immunohistochemical stain for β-catenin





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

Immunofluorescence stain of Keratinocytes

Yellow: E-cadherin, red: actin




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-mesenchymaltransition is often induced bystromal 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)


NF-kB signaling was necessary for EMT in the EpRas cell line

TNF-α and TGF-β contribute to active NF-kB signaling




Transgenic mice model

TAM(+) TAM (-)

Colony stimulating factor -1 (CSF-1) for recruit tumor associated macrophages

(TAM)

The effect of stromal macrophages on the invasive and metastatic

behavior of cancer cells


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 bytranscription factors that orchestratekey 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




Slug suppress E-cadherin transcription

Expression of EMT-inducing embryonic transcription factors in human tumors








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)


Red: fibroblast

Green: degraded

collagen IV

The ability of tumor cells to degrade collagen IV fibers

trough interaction with fibroblasts




Elevated MMP-2imparted increased

invasiveness to the

breast cancer cells

Macrophages are important source of MMPs

Section 6.

Extracellular proteases play keyroles in invasiveness





Tumor-

associated

macrophages




VEGF expression in TAMVEGF expression in tumor cells





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




uPA: urokinase

plasminogen

activator

Activation of extracellular proteins: MMPs and TGF-β by uPA and uPAR

Section 7.

Small Ras-like GTPases controlcellular processes includingadhesion,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.




Breast cancer cells Green: actin

The addition of heregulin induce the development of

lamellipodia that faces all directions


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 uselymphatic vessels to disperse fromthe 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 theorgan sites in which disseminatedcancer cells form metastases


Primary tumors and their metastatic tropisms




Section 10.

Metastasis to bone requires thesubversion of osteoblasts andosteoclasts




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)





osteoprotegerin

The physiologic balance between bone formation and resorption


The bone matrix

is a rich source of

mitogenic and

trophic factors

Parathyroid hormone

related peptides

The vicious cycle of osteolytic metastasis




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 genescontribute to regulating themetastatic phenotype




Section 12.

Occult micrometastases threatenthe long-term survival of cancerpatients




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

capitulo de biolgia del cancer

Documents

Transcript of capitulo de biolgia del cancer