Hebrew University researchers discover how a single gene can keep malignant cells from spreading to healthy tissue.


Reprinted with permission of Nature, Macmillan Publishers 2011
The red cells, tumor “micro-islands,” express a p53-suppressed gene. The green cells are rapidly proliferating due to p53 deficiency.

It is called simply p53, a short name that belies its starring role in halting the spread of cancer.

Israeli scientists already knew that when it is activated, the p53 gene produces a protein that can halt and even kill cancerous cells. Now, a team headed by Prof. Yinon Ben-Neriah and Dr. Eli Pikarsky of the Institute for Medical Research Israel-Canada at the Hebrew University of Jerusalem have discovered that p53 also governs a mechanism that keeps those deadly cells from invading healthy epithelial tissue lining the cavities and surfaces of many internal organs.

As the researchers described in the February issue of the journal Nature, the ability to “turn on” p53 could be a critical means of protection against colorectal and other epithelial forms of cancer.

Engineered mice yield surprising discovery

Building on earlier p53 studies by Dr. Moshe Oren of the Weizmann Institute of Science, who joined the current research team, Hebrew University doctoral students Ela Elyada and Ariel Pribluda spent six painstaking years engineering a unique mouse model to study the effect of p53 on the cell-invasion process.

“53 has been known for 20-something years as a gene that protects against cancer by suppressing tumors,” Ben-Neriah explains to ISRAEL21c. “It has several mechanisms to do this, and you can observe these phenomena even in a tissue culture dish.”

But his team wanted to go deeper. After developing a model that mimics colorectal cancer in mice and removing their p53 gene, the researchers saw something never before observed: malignant cells began invading neighboring cells at a fast clip.

“One of the earliest signs of cancer progression is this invasion process,” says Ben-Neriah. “Normally, it is slow. In humans, it takes 10 to 15 years for colorectal cancer to develop. Even in mouse models, it takes at least six months. But when we knocked out 53, we started observing the malignant process within seven days, and it happens throughout the gut. There was something fundamental going on that had to do with 53.”

Using sophisticated tools to analyze DNA and gene expression, the researchers found specific genes that kick off the invasion process. And when p53 is activated, it keeps those invasion-activating genes in check.

Better and faster way to diagnose cancer

Pikarsky, one of Israel’s leading pathologists, thinks it could be possible to use invasion-activating genes as diagnostic biomarkers for determining if a tumor is contained (benign) or invasive (malignant) at a very early stage.

Current methods cannot make this determination before the malignant cells have already invaded surrounding tissue, typically lymph nodes.

“Using the biomarker, we could have a chance to find out without going to the lymph nodes, and that would be a tremendous advantage,” says Ben-Neriah. Survival rates could be greatly enhanced if treatment started so early, and people with benign tumors would get the good news much sooner.

Another possible application of their discovery — though Ben-Neriah says it’s still just wishful thinking — would be to boost the group-control function of p53 to keep benign tumors from developing a spreading capacity. This idea is now being studied at the Hebrew University researchers’ labs.

Yissum, the Hebrew University’s technology transfer company, is lining up investors for human studies to begin this summer at Hadassah Medical Center on breast cancer patients and in Japan on gastric cancer patients.

The research was primarily funded by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Israel Science Foundation.