Cell-surface protein controls aggressiveness of cancer

By: Neil Neumann

Posted: 3/13/08

A team of researchers led by Stephen Baylin, a professor of oncology at the Hopkins School of Medicine, has recently uncovered an important factor in the severity of pancreatic cancer.

His group has characterized the molecular distinctions between localized and aggressive pancreatic cancer. Insights found stemming from this research will provide new avenues for pancreatic cancer treatments.

Pancreatic cancer is one of the deadliest forms of cancer. Roughly 40,000 people will be newly diagnosed this year and 35,000 will die from it, making it the fourth-leading cause of cancer deaths. Although it may not be the most prevalent of cancer, it is deadly: Only 5 percent of patients are alive 5 years after diagnosis.

One reason pancreatic cancer is so deadly is because most cases are not diagnosed until the cancer is fully progressed. If a cancer reaches this stage, treatment options are limited.

Most of the research into pancreatic cancer has focused on the primary tumors in patients as opposed to the more advanced disease, which actually kills the patients.

Also, even though 80 percent of pancreatic cancers are unresectable, meaning they cannot be removed by surgery, research has generally focused on those that can be removed.

This bias has led to poor understanding of the molecular biology of the most clinically relevant pancreatic cancers. This is where Baylin and his team stepped in to determine the role of the E-Cadherin protein and its implications in pancreatic cancers.

E-Cadherin is a transmembrane protein that is involved in cell-to-cell adhesion or linkages. E-Cadherin is found in epithelial tissue including the intestines and pancreas.

It has been known that loss of E-Cadherin expression correlates with progression of cancers to a more advanced stage.

It is thought that loss of this protein allows the cells to be more mobile, thus allowing them to escape the primary tumors and metastasize or spread to other parts of the body. It is important to understand this process of E-Cadherin loss because 90 percent of cancer deaths are the result of metastases.

Baylin and his group wanted to study the differences between those pancreatic cancers that express and do not express E-Cadherin. He first defined two categories of pancreatic cancers - cohesive and non-cohesive.

The first has E-Cadherin expression and forms glands and ducts in the tumor. Non-cohesive do not have E-Cadherin expression and also does not form glands nor ducts.

The next step in the research was to show that when the cancers turn from cohesive to non-cohesive, there is a specific loss of E-Cadherin rather than a more general loss of all related epithelial markers.

They showed that E-Cadherin was specifically lost and not other markers of cancer in pancreatic cells.

Finally, the researchers wanted to show a possible mechanism underlying the loss of E-Cadherin.

They first looked to see if the E-Cadherin gene was mutated and found that it was not. Loss of E-Cadherin expression is not the result of it being mutated.

They looked further at epigenetic markers associated with the E-Cadherin gene. What they found is that the E-Cadherin genes of the non-cohesive pancreatic cancers had methylated promoter sequences.

Methylation is a process in much multiple carbon groups are added to the beginning of a DNA sequence of a gene to silence it, preventing its expression into protein.

The cohesive cancers had no methylation in E-Cadherin. These cells were expressing E-Cadherin and had made no effort to block the corresponding gene.

These results show for the first time a possible underlying molecular mechanism involved in making a pancreatic cancer more aggressive.

The researchers also took frozen tissue samples from patients with different pancreatic cancers and looked for E-Cadherin expression. Those that had E-Cadherin loss also had decreased survival times compared to those patients with little or no loss of E-Cadherin.

This finding shows that E-Cadherin is a clinically relevant marker that can be used to look at the progression of the cancer.

With this new knowledge, Baylin and his team hope to create new therapies targeting the progression of pancreatic cancers using E-Cadherin as their focus.