Posts Tagged ‘although’

Enzyme controlling metastasis of breast cancer identified

“The take-home message of the study is that we have found a way to target breast cancer metastasis through a pathway regulated by an enzyme,” said lead author Xuefeng Wu, PhD, a postdoctoral researcher at UC San Diego.

The enzyme, called UBC13, was found to be present in breast cancer cells at two to three times the levels of normal healthy cells. Although the enzyme’s role in regulating normal cell growth and healthy immune system function is well-documented, the study is among the first to show a link to the spread of breast cancer.

Specifically, Wu and colleagues with the UC San Diego Moores Cancer Center found that the enzyme regulates cancer cells’ ability to transmit signals that stimulate cell growth and survival by regulating the activity of a protein called p38 which when “knocked down” prevents metastasis. Of clinical note, the researchers said a compound that inhibits the activation of p38 is already being tested for treatment of rheumatoid arthritis.

In their experiments, scientists took human breast cancer cell lines and used a lentivirus to silence the expression of both the UBC13 and p38 proteins. These altered cancer cells were then injected into the mammary tissues of mice. Although the primary tumors grew in these mice, their cancers did not spread.

“Primary tumors are not normally lethal,” Wu said. “The real danger is cancer cells that have successfully left the primary site, escaped through the blood vessels and invaded new organs. It may be only a few cells that escape, but they are aggressive. Our study shows we may be able to block these cells and save lives.”

Researchers have also defined a metastasis gene signature that can be used to evaluate clinical responses to cancer therapies that target the metastasis pathway.

source : http://www.sciencedaily.com/releases/2014/09/140902205145.htm

Long-term colorectal-cancer mortality after adenoma removal

BACKGROUND

Although colonoscopic surveillance of patients after removal of adenomas is widely promoted, little is known about colorectal-cancer mortality among these patients.

METHODS

Using the linkage of the Cancer Registry and the Cause of Death Registry of Norway, we estimated colorectal-cancer mortality among patients who had undergone removal of colorectal adenomas during the period from 1993 through 2007. Patients were followed through 2011. We calculated standardized incidence-based mortality ratios (SMRs) using rates for the Norwegian population at large for comparison. Norwegian guidelines recommended colonoscopy after 10 years for patients with high-risk adenomas (adenomas with high-grade dysplasia, a villous component, or a size ≥10 mm) and after 5 years for patients with three or more adenomas; no surveillance was recommended for patients with low-risk adenomas. Polyp size and exact number were not available in the registry. We defined high-risk adenomas as multiple adenomas and adenomas with a villous component or high-grade dysplasia.

RESULTS

We identified 40,826 patients who had had colorectal adenomas removed. During a median follow-up of 7.7 years (maximum, 19.0), 1273 patients were given a diagnosis of colorectal cancer. A total of 398 deaths from colorectal cancer were expected and 383 were observed, for an SMR of 0.96 (95% confidence interval [CI], 0.87 to 1.06) among patients who had had adenomas removed. Colorectal-cancer mortality was increased among patients with high-risk adenomas (expected deaths, 209; observed deaths, 242; SMR, 1.16; 95% CI, 1.02 to 1.31), but it was reduced among patients with low-risk adenomas (expected deaths, 189; observed deaths, 141; SMR, 0.75; 95% CI, 0.63 to 0.88).

CONCLUSIONS

After a median of 7.7 years of follow-up, colorectal-cancer mortality was lower among patients who had had low-risk adenomas removed and moderately higher among those who had had high-risk adenomas removed, as compared with the general population. (Funded by the Norwegian Cancer Society and others.)

source : http://www.sciencedaily.com/releases/2014/08/140828090156.htm

New enzyme targets for selective cancer therapies

Work happening in a University of Alberta chemistry lab could help find new and more selective therapies for cancer. Researchers have developed a compound that targets a specific enzyme overexpressed in certain cancers — and they have tested its activity in cells from brain tumours.

Chemistry professor Christopher Cairo and his team synthesized a first-of-its-kind inhibitor that prevents the activity of an enzyme called neuraminidase. Although flu viruses use enzymes with the same mechanism as part of the process of infection, human cells use their own forms of the enzyme in many biological processes.

Cairo’s group collaborated with a group in Milan, Italy, that has shown that neuraminidases are found in excess amounts in glioblastoma cells, a form of brain cancer.

In a new study, a team from the University of Milan tested Cairo’s enzyme inhibitor and found that it turned glioblastoma cancer stem cells — found within a tumour and believed to drive cancer growth — into normal cells. The compound also caused the cells to stop growing, suggesting that this mechanism could be important for therapeutics. Results of their efforts were published Aug. 22 in the Nature journal Cell Death & Disease.

Cairo said these findings establish that an inhibitor of this enzyme could work therapeutically and should open the door for future research.

“This is the first proof-of-concept showing a selective neuraminidase inhibitor can have a real effect in human cancer cells,” he said. “It isn’t a drug yet, but it establishes a new target that we think can be used for creating new, more selective drugs.”

Long road from proof of concept to drug

Proving the compound can successfully inhibit the neuraminidase enzyme in cancer cells is just the first step in determining its potential as a therapy.

In its current form, the compound could not be used as a drug, Cairo explained, largely because it wasn’t designed to breach the blood-brain barrier making it difficult to reach the target cells. The team in Milan had to use the compound in very high concentrations, he added.

The research advances our understanding of how important carbohydrates are to the function of cells. Although most of us think of glucose (blood sugar) as the only important sugar in biology, there is an entire area of research known as glycobiology that seeks to understand the function of complex carbohydrate structures in cells. Carbohydrate structures cover the surface of cells, and affect how cells interact with each other and with pathogens.

“The carbohydrates on the cell surface determine how it interacts with other cells, which makes them important in cancer and other diseases. So, if we can design compounds that change these structures, we can affect those interactions.” — Christopher Cairo, U of A

Scientists have known for decades that the carbohydrates found on cancer cells are very different from those on normal cells. For example, many cancers have different amounts of specific residues like sialic acid, or may have different arrangements of the same residues.

“The carbohydrates on the cell surface determine how it interacts with other cells, which makes them important in cancer and other diseases. So, if we can design compounds that change these structures in a defined way, we can affect those interactions,” Cairo explained. “Finding new enzyme targets is essential to that process, and our work shows that we can selectively target this neuraminidase enzyme.”

Although there has been a lot of work on targeting viral neuraminidase enzymes, Cairo’s team has found inhibitors of the human enzymes. “The challenge in human cells is that there are four different isoenzymes. While we might want to target one for its role in cancer, hitting the wrong one could have harmful side-effects,” he said.

The U of A team reached out to their colleagues in Milan who were studying the role of a specific neuraminidase isoenzyme in cancer cells isolated from patients. Cairo approached them about testing a compound his team identified last year, which was selective for the same isoenzyme.

“I expected it would do something, but I didn’t know it would be that striking. It came out beautifully,” Cairo said.

The U of A team is already working on improving the compound, and developing and testing new and existing inhibitors using a panel of in vitro assays they developed.

“We’ve been working on these enzymes for about five years. Validation of our strategy­­­ — design of a selective neuraminidase inhibitor and application in a cell that overexpresses that enzyme — is an achievement for us.”

source : http://www.sciencedaily.com/releases/2014/08/140822132932.htm