Research led by investigators from Vanderbilt-Ingram Cancer Center and the Vanderbilt Eye Institute suggests that the protein BVES (blood vessel endocardial substance) – which also is key in regulating corneal cells – may be a therapeutic target for halting colon cancer metastasis.
The study, appearing in the October issue of the Journal of Clinical Investigation, further suggests that BVES may be important more broadly in many, or most, epithelial cancers.
About 85 percent of cancers originate in epithelial cells that form the body's external and internal linings (such as the skin and the lining of the gastrointestinal tract).
However, the main clinical concern is not the primary tumor, but the potential for that tumor to leave its tissue of origin and spread throughout the body (a process called "metastasis").
A critical step in metastatic progression of epithelial cancers happens when epithelial cells "revert" to a less differentiated state – a process called "epithelial-mesenchymal transition" or EMT.
Ophthalmologist Min Chang, M.D., studies the healing process in the cornea, perhaps the most highly regulated epithelium in the body. From collaborative studies with David Bader, Ph.D., who discovered BVES and showed its importance in heart development, Chang found that BVES was highly expressed and regulated in corneal cells.
When BVES is disrupted in corneal cells, they become disorganized, almost "cancer-like," noted Chang, an assistant professor of Ophthalmology and Visual Sciences and co-author on the study.
Chang then brought these findings to the attention of colleague Christopher Williams, M.D., Ph.D., assistant professor of Medicine and Cancer Biology and co-author on the study.
"When he described these cells, it sounded a lot like the way cancer cells looked when they were undergoing metastasis," Williams said. "So it seemed reasonable to look in cancer for BVES-dependent phenotypes."
Chang and Williams teamed up with the lab of Daniel Beauchamp, M.D., to assess BVES expression in human colorectal cancers. They found that BVES levels were very low in all stages of colon cancer. They also noted decreased BVES levels in many other types of epithelial cancers (including breast) and in several colorectal cancer cell lines.
To uncover why BVES levels were reduced, the investigators enlisted the help of Wael El-Rifai, M.D., Ph.D., and colleagues. They determined that the BVES promoter (a DNA region that controls gene expression) was heavily modified (methylated), which silenced its expression. In cell experiments, the researchers showed that treating cells with a "demethylating" agent (the drug decitabine, which is currently used to treat myelodysplastic disorders) restored BVES expression. When BVES was expressed in colorectal cancer cell lines, they became more epithelial in nature and their tumor-like characteristics (in cell experiments and in animal models) decreased.
These findings suggest that treatment with agents to increase BVES levels might provide a way to decrease aggressive behaviors of colorectal and other epithelial cancers.
"In cancer, typically the primary tumor doesn't kill you; it's the metastatic disease that proves lethal," said Williams. "So if targeting BVES could interfere with metastasis, that would be very exciting."
The researchers also identified signaling pathways involved in BVES function that may represent other therapeutic targets – and that reveal new insights into the normal biological function of BVES. The findings could have implications in wound healing and other normal functions of epithelial cells, as well as for many types of epithelial cancer.
"We don't think it's just isolated to the colon; it pertains to a broad lot of epithelial cancers," Chang noted. "And that's a lot of cancers."
The research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, National Center for Research Resources, National Institute of General Medical Sciences, and the National Eye Institute.
Melissa Marino | EurekAlert!
23.03.2017 | Technische Universität München
How prenatal maternal infections may affect genetic factors in Autism spectrum disorder
22.03.2017 | University of California - San Diego
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Earth Sciences
24.03.2017 | Life Sciences
23.03.2017 | Life Sciences