UCSF LogoUCSF scientists have shown for the first time that the severity of a tissue could perhaps stimulate cancer. They were believed to have recognized an enzyme that is essential for regulating tissue stiffness. Further, they demonstrated that the enzyme may be able to turn abnormal but non-malignant breast tissue into tumors.

Blocking the enzyme lysyl oxidase (LOX) seemed to have reduced tissue stiffness and lessened the risk a tumor would form. In addition, it also appeared to have caused tumors that did develop to be smaller and less aggressive. The supportive tissue neighboring cancer cells seemed to have been shaped in a different way as compared to healthy tissue. Apparently, they were stiffer and more fibrous. These properties may perhaps assist doctors in detecting breast cancers. However, till today scientists were observed to have not valued that these physical changes in fact control tumor development. Additionally, no one has yet recognized factors that regulate these modifications.

In the existing study, the authors found that the enzyme LOX may perhaps have caused many of the structural changes in collagen to alter in a process called as cross-linking. More so, collagen is known to be the major component of the supportive tissue. In experimental models, higher levels of LOX appeared to have increased the amount of collagen cross-linking in the mammary glands. Apparently this in turn made the tissue stiffer and connected with a higher frequency of tumors invading the breast tissue.

Later, the team was noted to have made use of chemicals or an antibody to block LOX. They found that collagen in the mammary glands seemed to have contained fewer cross-links and the tissue was less fibrous and softer. Most important, they found fewer and smaller tumors appeared to have formed in breast tissue and the tumors that did form were of a lower grade i.e. less aggressive.

“Our study shows how stiffening of the breast tissue that is controlled by enzymes such as LOX is a key process that regulates cancer development,’’ says senior author Valerie Weaver, PhD, associate professor and director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery at the University of California, San Francisco.

Weaver also an associate professor in the Department of Anatomy and the new Department of Bioengineering and Therapeutic Sciences at UCSF further said that, “These findings suggest that any factor that increases the stiffness in a tissue could promote cancer. The most compelling finding of the study is that the research team identified enzymes that regulate tissue stiffening—opening up the possibility for the development of targeted therapies. The enzyme triggers a clear physical change in breast tissue and, if we could stop this happening, we expect it would prevent cancers from progressing and hopefully also prevent tumor metastasis which is the leading cause of patient mortality.”

The findings evidently demonstrated that LOX activity may be able to increase collagen cross-linking to stiffen the tissue. Moreover, it is the stiffness that seems to drive the pre-cancerous cells to turn into invasive tumors. The study supposedly explains previous observations that implicated LOX in tumor metastasis. However, contrary to those earlier studies, the present study seems to emphasize the vital role of early changes in the tissue microenvironment induced by LOX.

The findings of the study are noted to have been built upon past work conducted by the authors that implicated integrins as signaling molecules that play a crucial role in directing the cancerous behavior of a tissue. Integrins are known to be receptors that assist in mediating attachment between a cell and surrounding tissue. The findings also suggest why human tumors that are typically stiffer than normal tissue so often have high integrin activity.

Although the tests were carried out in breast cancer, there appears to be compelling evidence from the authors that suggest a similar mechanism possibly operates in many other cancers. For example, pancreatic tumors are believed to be notoriously very firm and extremely aggressive. Weaver and colleagues newly found that pancreatic tumors could perhaps have high levels of LOX in their connective tissue i.e. stroma.

Weaver claimed that the unique perspective of the UCSF study is that until recently, most scientists have focused only on the tumor cells themselves. Whereas the authors in this study showed that it is the cells inside the connective tissue adjacent to the growing tumors that seem to express the LOX enzyme. Moreover, these cells were observed to induce the tissue stiffening and fibrosis that then, via mechanical forces, promote the tumor cells to become invasive.

These observations may perhaps be significant because they emphasize the need to treat tumors early and to focus on the tissue microenvironment and not only the tumor but the surrounding area too. Also, cross-linking and stiffness in supporting tissue in general appears to be important in tumor progression. Further, the findings imply that other enzymes and molecules that support this process may also be able to promote cancer formation.

Further testing has established other factors that could perhaps act in combination with LOX, including cancer genes such as ErbB2 and other molecules including PI3kinase. Moreover, the study shows that cancer may be best viewed as a complex process of changes in tissue remodeling that is tightly controlled by many biochemical and mechanical factors.

The findings of the study have been published in the online journal of Cell.