metastasis figure 20-1 molecular biology of the cell (© garland science 2008) metastatic tumors
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Metastasis
Figure 20-1 Molecular Biology of the Cell (© Garland Science 2008)
Metastatic tumors
Cancer develops through gradual changesin cell morphology and properties
benign tumor
malignant tumor
You may not believe it but by the end of the semesterThis will make sense!
Hanahan and Weinberg, Cell 100:57-70 (2000)
Where do they go?
Figure 14.42 The Biology of Cancer (© Garland Science 2007)
Metastatic tropism
Metastatic tropism
- Cells find their way to the target tissue via
-
Figure 14.17b The Biology of Cancer (© Garland Science 2007)
Metastasis
An organ is composed of several tissues
Epithelial cells
Connective tissue
Muscle tissue
Cancer cells need to change their epithelial properties, to lose their adhesion and to
penetrate through potent physical barriers
basal lamina connective tissue
How do they do that?
The same way normal cells do it
Figure 14.17b The Biology of Cancer (© Garland Science 2007)
Metastasis
Intravasation
Figure 14.17b The Biology of Cancer (© Garland Science 2007)
Metastasis
The blood: a hostile environment
Figure 14.7b The Biology of Cancer (© Garland Science 2007)
http://www.cancerquest.org/
- Cells are normally anchorage-dependent (anoikis)- Shear forces tear cells apart
Figure 14.10a The Biology of Cancer (© Garland Science 2007)
Colonization
First, micrometasteses
Figure 14.12 The Biology of Cancer (© Garland Science 2007)
Dormant micrometasteses are viable
Figure 14.50a The Biology of Cancer (© Garland Science 2007)
Steeg Nature Med 06
Angiogenesis
Eventually: macrometastases
Intravasation
Latency
Colonization
Nguyen, Nature Rev. Cancer 2009
Figure 20-44 Molecular Biology of the Cell (© Garland Science 2008)
A sequence of inefficient steps
Metastatic inefficiency
How do cells become invasive?
Back to the first steps
Figure 14.13a The Biology of Cancer (© Garland Science 2007)
EMTEpithelial to Mesenchymal Transition
sea urchin embryo
EMTEpithelial to Mesenchymal Transition
Major changes during EMT
- Loss of E-cadherin
- Cell shape changes driven by Rho GTPases
- MMPs
Figure 13.12d The Biology of Cancer (© Garland Science 2007)
cadherinactin
Figure 14.15b The Biology of Cancer (© Garland Science 2007)
Adopting changes typical to EMT
Figure 14.19c The Biology of Cancer (© Garland Science 2007)
Epithelial marker
Mesenchymal marker
Rho family proteins promote actin remodeling
Svitkina and Borisy JCB 99
MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM
Major changes during EMT
- Loss of E-cadherin
- Cell shape changes driven by Rho GTPases
- MMPs
Epithelial marker
Mesenchymal marker
Figure 14.20e The Biology of Cancer (© Garland Science 2007)
Figure 14.25 The Biology of Cancer (© Garland Science 2007)
AngiogenesisMMP-9
To learn more about the interactions between cancer cells and their microenvironment:
2 review papers posted on your website under “other material”
Summary
- Invasion-intravasation-circulation-extravasation-colonization
- Metastatic cells follow the EMT program
- Metastasis is inefficient
- Tumor cells rely on stromal cells in their microenvironment
- Major changes: cell adhesion, cell shape changes, and secretion of MMPs