Tissue Stiffness is Key to Aggressive Cancers

Thursday 19 November 2009

Scientists have identified an enzyme that is crucial for turning abnormal but non-malignant breast tissue into tumours, according to a study published today in Cell online. The study was led by Professor Valerie Weaver from the University of California, San Francisco http://news.ucsf.edu/releases/tissue-tension-regulates-tumor-progression/.

Blocking the enzyme lysyl oxidase (LOX) reduced the chance a tumour would form, and also meant tumours that did develop were smaller and less aggressive.

“Our study shows that stiffening of the breast tissue controlled by enzymes such as LOX are a key factor in cancer development, suggesting these enzymes are a promising candidate drug target,” study co-author Dr Janine Erler from The Institute of Cancer Research in the UK says. “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.”

The supportive tissue surrounding cancer cells is shaped differently to healthy tissue as well as stiffer and more fibrous. These properties help doctors detect breast cancers, but until now scientists have not known what was causing these modifications.

In the latest study, the team found LOX caused the structure of collagen, the major component of the supportive tissue, to change in a process known as cross-linking. In experimental models, higher levels of LOX increased the levels of collagen in mammary glands, made the tissue stiffer and correlated with a higher frequency of tumours invading the breast tissue.

When the team used chemicals or an antibody to block LOX, they found collagen in the mammary glands contained fewer cross-links and the tissue was less fibrous. Most importantly, they found fewer and smaller tumours had formed in breast tissue and the tumours that did form were of a lower grade (less aggressive).

Dr Erler’s previous studies have already highlighted the importance of LOX in cancer spread, showing that it promotes metastasis by sending out signals that prepare a new area of the body for invasion. The new study shows that LOX is also crucial for primary tumour progression.

Although the tests were carried out in breast cancer, Dr Erler says it is likely a similar mechanism occurs in other cancer types as LOX levels are known to be elevated in many cancer types. Until recently, however, most investigators have focused only on the tumour cells themselves. What makes the current study so unique is that the investigators showed that it is the cells within the connective tissue surrounding the growing tumours that express the LOX enzyme. These cells induce the tissue stiffening and fibrosis that then, through mechanical forces, promote the tumour cells to become invasive. These observations are significant because they emphasize the need to treat tumours early and to focus on the tissue microenvironment – not just the tumour but the surrounding area too.

The findings also suggest that cross-linking and stiffness in supporting tissue in general is important in tumour progression, and imply that other enzymes and molecules that support this process could also promote cancer formation.

“This study may also help explain why the rate of breast cancer increases dramatically with age - aged tissues are stiffer and contain higher levels of abnormal collagen cross-links,” study lead researcher Professor Valerie Weaver from the University of California, San Francisco, says. “I’m cautiously optimistic. We still have a lot more work to do, but this is certainly exciting.”

Further testing established other factors that could be acting in combination with LOX, including cancer genes such as ErbB2 and other molecules including PI3kinase. Professor Weaver says the study shows that cancer is best viewed as a complex process of changes in tissue remodelling that is tightly controlled by many biochemical and mechanical factors.

Scientists from the University of Pennsylvania, University of California, San Francisco, Stanford University School of Medicine, University of Hawaii at Manoa and the University of North Carolina also contributed to this study.

-ENDS-

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