How Cancer Cells Coax Fibroblasts Into Enabling Metastasis

An interaction between two proteins empowers cancer cells to use the physical forces of healthy cells to start spreading to other parts of the body, researchers from the Francis Crick Institute in London and the Institute for Bioengineering of Catalonia (IBEC) in Barcelona have discovered.

The process by which cancer cells separate from the original tumor to form new tumors in other organs or tissues of the body is called metastasis, and it is responsible for the majority of deaths in patients with cancer.

The research team identified a mechanism by which cancer cells manage to escape the tumor to promote metastasis. They revealed that tumor cells can reprogram their healthy neighbors, dragging them out of the tumor and into other tissues.

Hijacked Fibroblast Cells

The victims of this ‘kidnapping’ are fibroblasts, a cell type that is responsible for the synthesis and organization of the extracellular matrix – the scaffolding in which cells reside and which helps give structure to tissues in the body. Anna Labernadie of IBEC and first author of the study, said:

“Fibroblasts are professionals in maintaining healthy tissues, and are able to create tunnels in the tissues to travel through. They use this ability to restore the tissues when we suffer an injury.”

Many cancers initially have a very limited ability to invade the tissue around them. But over time they find the mechanism to do so, increasing the aggressiveness of the cancer.

The researchers, led by Xavier Trepat at IBEC and Erik Sahai at the Crick, showed that cancer cells use the mobility of fibroblasts to escape the tumor and travel through tissues. The surrounding tumor, or stroma, modifies the fibroblasts and uses them for the invasion into other tissues.

From this point, the fibroblasts start to serve the cancerous cells, tracing paths for them through the extracellular matrix surrounding the tumor.

E-cadherin And N-cadherin

The scientists have now shown that fibroblasts not only create tunnels beyond the stroma, but exert physical forces to drag cancer cells through these tunnels, promoting the invasion of healthy tissue.

“It’s like a train: the fibroblasts are locomotives and the cancer cells are wagons,” says Labernadie.

The group were able to identify the mechanism by which cancer cells stick to fibroblasts and move together. It is down to an interaction between two different proteins, one located on the surface of cancer cells called E-cadherin, and another expressed on the surface of fibroblasts, called N-cadherin.

“These proteins are the nanoscale hooks that enable cells to join together. Until now, we knew very little about this interaction”, says Xavier Trepat of IBEC.

The researchers used cells and tissues obtained from patients with lung and skin cancer.

“We identified this mechanism in very different tumors, which suggests that it may be universal,” stresses Xavier. “Because of the poor prognosis for patients who have suffered cancer metastasis, identifying the mechanisms that promote tumor growth can help us find ways to stop it.”

Anna Labernadie, Takuya Kato, Agustí Brugués, Xavier Serra-Picamal, Stefanie Derzsi, Esther Arwert, Anne Weston, Victor González-Tarragó, Alberto Elosegui-Artola, Lorenzo Albertazzi, Jordi Alcaraz, Pere Roca-Cusachs, Erik Sahai & Xavier Trepat
A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion
Nature Cell Biology (2017) doi:10.1038/ncb3478

Image: Cancer cells (green) and cancer-associated fibroblasts (CAFs, in red) invading an extracellular matrix. Credit: Takuya Kato

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