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Cooperative invasion of tumour cells

Metastases are the leading cause of cancer-associated deaths. A European project studied how cells that surround tumours may contribute to the process of cell invasion.
Cooperative invasion of tumour cells
Cancer progression is increasingly attributed to the aberrant interaction between cancer cells and their microenvironment. Research on the cooperation between stromal and cancer cells has mainly focused on the effects of diffusible factors like cytokines and growth factors involving these cell types. The EU-funded CAFFORCE (Physical forces driving fibroblast-led cancer cell migration) project identified a cooperative invasion mechanism of physical force exerted by cancer associated fibroblasts (CAFs) on cancer cells.

Researchers demonstrated that the interaction between CAFs and cancer cells is mediated by a heterophilic junction between the adhesion molecules – E-cadherin on cancer cells and N-cadherin on CAFs. In contrast with traditional understanding that expression of cadherins by adjacent tissues leads to segregation, an E-cadherin/N-cadherin interaction enabled cancer cell adhesion, migration, and invasion.

Project results established that heterotypic junctions are able to trigger mechanotransduction pathways. It was supported by the recent observation that an E-cadherin/N-cadherin junction between cancer cells and osteogenic cells promotes Akt signalling. The Akt signal transduction pathway promotes survival and growth in response to extracellular signals.

The heterophilic E-cadherin/N-cadherin junction also triggered repolarisation of the CAFs, favouring their migration away from the potential tumour. In contrast, force transmission through homophilic E-cadherin junctions mediates adhesion but does not trigger migration away from cell-cell contacts.

In conclusion, CAFFORCE established that a physical interaction through a heterophilic E-cadherin/N-cadherin junction enables the cooperative invasion of CAFs and cancer cells. CAFs support invasion of cancer cells by pulling them away from the tumour, while cancer cells further enhance their spread by redirection of CAF migration away from the tumour.

Related information


Metastases, cell invasion, CAFFORCE, cancer associated fibroblasts, cadherins
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