Blocking tissue stiffening enzyme could be key to preventing aggressive cancers


Blocking tissue stiffening enzyme could be key to preventing aggressive cancers

A team of scientists from the US and the UK have shown that blocking an enzyme called lysyl oxidase (LOX) that causes tissue to stiffen reduces the likelihood of abnormal but non-malignant breast tissue turning into tumors, suggesting that LOX and similar enzymes could be new targets for effective anti-cancer drug therapies.

The study was the work of co-author Dr Janine Erler from The Institute of Cancer Research in the UK and colleagues and was published online in the journal Cell on 19 November.

Erler said in a press statement that their findings show that stiffening of breast tissue under the control of LOX and similar enzymes is a key factor in the development of cancer.

Evidence from previous studies by Erler and colleagues had already shown that LOX was important in cancer spread or metastasis, because it sends out signals that helps ready other body sites for invasion. With this new study they can add another role to the enzyme: it is also important for progression of the tumor itself.

They found that blocking the enzyme reduced the chances of tumors forming, and increased the likelihood that when they did develop, they were smaller and less aggressive.

"The enzyme triggers a clear physical change in breast tissue and, if we could stop this happening, we expect it would slow the growth of any cancers that did develop and make them easier to eradicate," said Erler.

The extracellular matrix (ECM) that supports cells has a different structure and a stiffer, more fibrous consistency in cancerous tissue compared to healthy tissue, and these characteristics help doctors detect breast cancers.

Scientists know quite a lot about how ECM remodels as cancer develops, but they don't know much about the stiffening process and what causes it.

Erler and colleagues found that LOX changed the structure of collagen, a major component of ECM, through a process called crosslinking.

In a series of experiments with LOX, they found that higher levels of the enzyme increased the levels of collagen in mammary glands, caused the tissue to become stiffer, and were linked with higher frequencies of tumors in the breast tissue.

When they blocked LOX via chemicals or antibodies, they found the collagen in the mammary glands had fewer crosslinks, the breast tissue was less fibrous, and perhaps more importantly, contained fewer tumours, and those that did form were of a lower grade, ie less aggressive.

Although their work focused on the role of LOX in breast cancer tissue, Erler suggests it may also play a role in the development of other types of cancer, as high levels of the enzyme have also been found linked with other types of tumor.

But until recently most studies have focused on the tumor cells themselves, and not on what is happening in surrounding tissue: a new insight now offered by this latest work, which appears to emphasize the importance of treating tumors early, and to focus on not just the cells but also their environment.

When they did further tests, the researchers also found that other factors could be working in conjuction with LOX, for instance the cancer gene ErB2 and other molecules like PI3kinase, suggesting that cancer is best viewed as a complex pattern of changes to tissue structure and composition that is tightly regulated by a multitude of biochemical and mechanical processes.

Co-author Professor Valerie Weaver from the University of California, San Francisco, said that the study might also clarify why breast cancer develops faster in older women:

"Aged tissues are stiffer and contain higher levels of abnormal collagen crosslinks."

Weaver called the findings "exciting" but described herself as "cautiously optimistic".

We still have a lot more work to do," she added.

"Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling."

Kandice R. Levental, Hongmei Yu, Laura Kass, Johnathon N. Lakins, Mikala Egeblad, Janine T. Erler, Sheri F.T. Fong, Katalin Csiszar, Amato Giaccia, Wolfgang Weninger, Mitsuo Yamauchi, David L. Gasser and Valerie M. Weaver.

Cell, 19 November 2009.

DOI:10.1016/j.cell.2009.10.027

Source: ICR.

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Section Issues On Medicine: Women health