Molecular basis of metastasis

Hallmarks of Cancer

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

Invasion and Metastasis

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

Cell Motility

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

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

Invadopodia and Cancer

• Malignant melanoma

• Breast /Mammary carcinoma

• Glioma

• Glioblastoma Multiforme

Tumours

• Head and neck squamous

cell carcinoma

Katz, Verleyen et al. 2011

Extravasation

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

“Escape of Cancer Cells from Circulation”

Q. What is extravasation of cancer cells?

Koop et al 1996

Leukocyte Adhesion Model

Adhesion to Integrins

Adhesion to Selectins

E-Selectins P-Selectins L-Selectins

Adhesion to IgSF Interaction with

Platelets Interaction with

Leukocytes

Selectin Pathways

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

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

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

Cancer Cell Survival

Evasion of the host defence

The Hallmarks of Cancer: The Next Generation

Hanahan & Weinberg 2011

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

Question: What methods do cancer cells

employ to evade the host defence?

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

2. Toll-Like Receptors

Cancer cells adopt characteristics of the host defence

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

2005 O Bohana-Kashtan - Profiling Tumour Counterattack

Clonal Selection Hypothesis

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

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