1. Metastasis Figure 20-1 Molecular Biology of the Cell (© Garland Science 2008) Metastatic tumors

2. Cancer develops through gradual changes in cell morphology and properties benign tumor malignant tumor

4. You may not believe it but by the end of the semester This will make sense! Hanahan and Weinberg, Cell 100:57-70 (2000)

5. Where do they go? Figure 14.42 The Biology of Cancer (© Garland Science 2007) Metastatic tropism

6. - Cells find their way to the target tissue via -

7. Figure 14.17b The Biology of Cancer (© Garland Science 2007) Metastasis

8. An organ is composed of several tissues Epithelial cells Connective tissue Muscle tissue

9. Cancer cells need to change their epithelial properties, to lose their adhesion and to penetrate through potent physical barriers basal laminaconnective tissue

10. How do they do that? The same way normal cells do it

11. Figure 14.17b The Biology of Cancer (© Garland Science 2007) Metastasis

12. Intravasation

13. Figure 14.17b The Biology of Cancer (© Garland Science 2007) Metastasis

14. 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

15. Figure 14.10a The Biology of Cancer (© Garland Science 2007) Colonization First, micrometasteses

16. Figure 14.12 The Biology of Cancer (© Garland Science 2007) Dormant micrometasteses are viable Figure 14.50a The Biology of Cancer (© Garland Science 2007)

17. Steeg Nature Med 06 Angiogenesis Eventually: macrometastases Intravasation Latency Colonization

18. Nguyen, Nature Rev. Cancer 2009

19. Figure 20-44 Molecular Biology of the Cell (© Garland Science 2008) A sequence of inefficient steps Metastatic inefficiency

20. How do cells become invasive? Back to the first steps

21. Figure 14.13a The Biology of Cancer (© Garland Science 2007) EMT Epithelial to Mesenchymal Transition sea urchin embryo

22. EMT Epithelial to Mesenchymal Transition

23. Major changes during EMT - Loss of E-cadherin - Cell shape changes driven by Rho GTPases - MMPs

24. Figure 13.12d The Biology of Cancer (© Garland Science 2007) cadherin actin

25. Figure 14.15b The Biology of Cancer (© Garland Science 2007) Adopting changes typical to EMT

26. Figure 14.19c The Biology of Cancer (© Garland Science 2007) Epithelial marker Mesenchymal marker

27. Rho family proteins promote actin remodeling Svitkina and Borisy JCB 99

28. MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM

29. Major changes during EMT - Loss of E-cadherin - Cell shape changes driven by Rho GTPases - MMPs

30. Epithelial marker Mesenchymal marker

31. Figure 14.20e The Biology of Cancer (© Garland Science 2007)

32. Figure 14.25 The Biology of Cancer (© Garland Science 2007)

33. Angiogenesis MMP-9

34. To learn more about the interactions between cancer cells and their microenvironment: 2 review papers posted on your website under “other material”

36. 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