Invadopodia play an important role in cancer cell invasion and metastasis. Key proteins involved in invadopodia include actin regulators like cortactin and N-WASP, and adaptor proteins like TKS4 and TKS5. Invadopodia allow cancer cells to degrade the extracellular matrix through metalloproteinases. Cancer cells employ various mechanisms to evade the host immune response after extravasation, including secreting TGFβ and expressing toll-like receptors and tumor counterattack proteins that can kill lymphocytes. Successful metastasis requires cancer cells to survive in the bloodstream, home to appropriate tissues, and overcome host defenses at the secondary site.

1. Molecular basis
of metastasis

2. Hallmarks of Cancer
Hanahan and Weinberg. Cell. 2011 Mar 4;144(5):646-74

3. Invasion and Metastasis
Talmadge and Fidler. Cancer Res. 2010 Jul 15;70(14):5649-69

4. Cell Motility
Sahai E. Curr Opin Genet Dev. 2005 Feb;15(1):87-96

5. Invadopodia
• Found in invasive cancer cells, vascular smooth muscle,
endothelial & immune cells
• ECM degradation
• Key proteins –
 Actin regulators- Cortactin & N-WASP
 Adaptor proteins- TKS4 & TKS5
 Metalloproteinases- MMPs

6. Invadopodia and Cancer
• Malignant melanoma
• Breast /Mammary carcinoma
• Glioma
• Glioblastoma Multiforme
Tumours
• Head and neck squamous
cell carcinoma
Katz, Verleyen et al. 2011

7. Extravasation
Source: Role of Cancer Microenvironmentin Metastasis: Focus on Colon Cancer. Gout,
Stéphanie; Huot, Jacques. Cancer Microenvironment 2009 Vol. 1 Issue 1

8. “Escape of Cancer Cells from
Circulation”
Q. What is extravasation of
cancer cells?
Koop et al 1996

9. Leukocyte
Adhesion Model

10. Adhesion to
Integrins
Adhesion to
Selectins
E-Selectins P-Selectins L-Selectins
Adhesion to IgSF
Interaction with
Platelets
Interaction with
Leukocytes
Selectin Pathways

11. Source: Biophysics of selectin–ligand interactions in inflammation and cancer. L
Cheung, PS Raman, EM Balzer, D Wirtz and Kkonstantopoulos. 2011 Phys. Biol. 8
015013

12. VEGF Degradation
•VEGF is produced and secreted by tumour cells
•Has a Src kinase domain
•Uncouples E-cadherin from β-catenin in the
endothelium
•Results in permeabilisation of the endothelium

13. Q. What makes cancer cells
more likely to extravasate at a
particular site?
•Pre-metastatic niche
•By upregulation of selectins in specific
microvasculature
• Expression of specific chemokine receptors

14. Cancer Cell Survival
Evasion of the host defence

15. The Hallmarks of Cancer: The Next Generation
Hanahan & Weinberg 2011

16. Turns out this is very hard to do....
Very few metastatic cells survive to establish secondary colonies
1. Destroyed in blood
2. ‘Seed’ doesn’t arrive at an appropriate ‘Soil’
3. Overwhelmed by the host defence
2008 Klein – The Metastatic Cascade

17. Question:
What methods do cancer cells
employ to evade the host defence?

18. 1. TGFβ Secretion
TGFβ  Scarring Cytokine
In Immune Response:
–Through cell-cell interactions,
cytotoxic T-Cells destroy target
cells via release of enzymes such
as Perforin
–If cancer cells harness the ability
to secrete it or get others
around them to secrete it – they
will have a growth and survival
advantage
–Transcriptionally represses the
production of their key cytotoxic
proteins
CTL
MHC 1
Perforin

19. 2. Toll-Like Receptors
Cancer cells adopt characteristics of the host defence

20. 3. “Tumour Counterattack”
Tumour cells may not only resist destruction by
the immune system passively –
May also actively kill infiltrating lymphocytes
Induces the lymphocyte Death Receptor

21. 2005 O Bohana-Kashtan - Profiling Tumour Counterattack

22. Clonal Selection Hypothesis
Talmadge and Fidler. Cancer Res. 2010 Jul 15;70(14):5649-69

23. Conclusion
• Ability to invade and metastasise defining
feature of malignancy
• Cells must acquire motility and the ability to
traverse basement membrane
• Cells must be able to survive in new tissue
• Involvement of multiple gene programs