Enzyme helps prepare lung tissue for metastatic development

Feb 16, 2011

A Massachusetts General Hospital (MGH) study has identified a new role for an important enzyme in preparing lung tissue for the development of metastases. Published in the early edition of Proceedings of the National Academy of Sciences, the report describes how focal adhesion kinase (FAK) is involved in producing areas of vascular leakiness in lung tissue – known to be part of the premetastatic process – and increases expression of a molecule that attracts cancer cells to potential metastatic sites.

"Blood from all tissues of the body travels to the lungs for oxygenation, increasing the likelihood that circulating metastatic cells will interact with the lung microvasculature," says Rakesh K. Jain, PhD, director of the Steele Laboratory for Tumor Biology at MGH and senior author of the study. "Identifying factors that prepare this 'hospitable soil' for tumor formation may help us develop strategies to slow or halt that process."

In order to form , cancer cells carried through the bloodstream need to find an environment that allows them to adhere and proliferate. While recent research supports the hypothesis that primary tumors secrete factors that prepare distant sites for potential metastatic development, defining the role of specific factors has been challenging. The current study investigated whether the ability of tumors in other parts of the body to induce formation of distinct areas of abnormal leakiness in contributes to the development of metastases.

The researchers first confirmed that either the presence of an implanted tumor or infusions of factors secreted by tumors produced localized areas of leakiness in the lungs of mice. Analysis of the tumor-secreted factors identified specific molecules known to increase vascular permeability, including the angiogenesis-inducing vascular endothelial growth factor (VEGF). Metastatic cells infused into mice treated with either tumor-secreted factors or VEGF preferentially adhered to sites of leaky lung tissue, and both this attraction of tumor cells and the increase in vascular permeability were reduced by blocking VEGF activity.

Since VEGF is known to activate FAK – which plays a role in cellular signaling – in the endothelial cells that line pulmonary blood vessels, the researchers analyzed levels of the enzyme at the sites of induced vascular leakiness and found them to be elevated. "Blocking the activity of FAK in lung endothelial cells reduced both vascular permeability and the adhesion of to those tissues. Additional genetic experiments revealed that FAK produces these effects through increased local expression of the cellular adhesion molecule E-selectin," says Dai Fukumura, MD, PhD, of the Steele Lab, a co-senior author of the report.

Co-senior author Dan G. Duda, DMD, PhD, also of the Steele Lab, adds, "Anti-metastatic therapy is the ultimate frontier for cancer therapy, but existing treatments – both traditional chemotherapy and newer antiangiogenesis agents – have limited effectiveness in preventing the development of metastases. Our findings provide proof of principle that FAK inhibition is a valid antimetastatic strategy that should be investigated in future translational studies."

Explore further: Muscular dystrophy: Repair the muscles, not the genetic defect

Related Stories

Tumors bring their own support cells when forming metastases

Dec 01, 2010

The process of metastasis requires that cancer cells traveling from a primary tumor find a hospitable environment in which to implant themselves and grow. A new study from Massachusetts General Hospital (MGH) Cancer Center ...

Potent metastasis inhibitor identified

Jun 22, 2009

Researchers at Children's Hospital Boston have isolated a potent inhibitor of tumor metastasis made by tumor cells, one that could potentially be harnessed as a cancer treatment. Their findings were published in the online ...

Normalizing tumor vessels to improve cancer therapy

Aug 25, 2008

Chemotherapy drugs often never reach the tumors they're intended to treat, and radiation therapy is not always effective, because the blood vessels feeding the tumors are abnormal—"leaky and twisty" in the words of the ...

Recommended for you

Dendritic cells affect onset and progress of psoriasis

Sep 12, 2014

Different types of dendritic cells in human skin have assorted functions in the early and more advanced stages of psoriasis report researchers in the journal EMBO Molecular Medicine. The scientists suggest that new strate ...

Approach to deadly sepsis infections continues to vary

Sep 12, 2014

Treatment practices for patients hospitalised with the potentially fatal infection known as "sepsis" will continue to vary because of individual differences between hospitals and countries, according to University of Adelaide ...

User comments : 0