BioWorld International Correspondent

LONDON - A molecule that plays a role in helping cells metastasize could provide an interesting target for those developing therapies against cancer. The molecule, called TrkB, allows cells to ignore signals that normally would induce apoptosis after they have left their normal environment.

The team of researchers in the Netherlands who made the discovery are keen to hear from potential commercial partners who could help them develop their work.

Daniel Peeper, assistant professor in the division of molecular genetics at the Netherlands Cancer Institute in Amsterdam, told BioWorld International: "This work provides us with a new and attractive drug target. We are now looking for ways to set up high-throughput drug screens of inhibitors that would kill the activity of TrkB."

But it could be five to 10 years before a drug could come on the market, Peeper cautioned. "It would only be a suitable treatment for those tumors where TrkB is expressed or mutated," he added. Those include aggressive neuroblastomas that have a poor prognosis, colon carcinomas and possibly prostate and pancreatic tumors.

TrkB is a tyrosine kinase receptor known to assist in the proliferation, differentiation and survival of certain cells of the nervous system. The work by Peeper and his colleagues shows that it also can suppress the ability of normal epithelial cells to undergo a specific form of apoptosis.

An account of the study appears in the Aug. 26, 2004, issue of Nature in a paper titled "Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB."

When normal cells become detached from their usual resting place, they undergo a specific type of apoptosis known as anoikis. (The word comes from the Greek for "homelessness.") Scientists can emulate anoikis by transferring cells in culture from petri dishes where they can adhere to the plastic, to dishes coated with a substance that does not allow them to stick to it. Cells put into the latter type of dish rapidly die.

Peeper said: "Genes that allow cells to ignore anoikis may play a role in metastasis. We decided to scan the mouse genome for such genes, by introducing gene fragments into rat intestinal epithelial cells using a retroviral vector, and then looking for cells that could survive the transfer into the dishes that normally induces anoikis."

Among the dying cells was one cluster that was very much alive. Investigations showed that the gene that had entered those cells encoded the protein TrkB.

The group's next experiment was to insert a copy of the TrkB gene into normal cells. After growing those in a dish, they were transferred to suspension culture - a change that, again, normally results in cell death by anoikis. In that case, the cells survived and thrived in the new environment. Control cells, engineered to contain a control gene, died. Those experiments allowed the team to validate TrkB as a true "hit" in the screening process.

To further test TrkB, Peeper and his colleagues engineered cells to express the TrkB gene and then injected those cells into nude mice. The mice developed large, aggressive tumors.

To find out whether TrkB had endowed the epithelial cells with metastatic potential, the group used noninvasive chemoluminescent imaging, which allowed them to view the positions and relative abundance of the engineered cells in the animals without the need to kill the animals.

After injecting the cells subcutaneously, the team could see that control cells (which did not contain the TrkB gene) failed to form tumors within 100 days of inoculation. However, TrkB-expressing cells had formed rapidly growing tumors that efficiently spread to the lymph vessels and lymph nodes and infiltrated distant tissues and organs, including the lungs. The results of that and further experiments showed, the authors wrote, "that TrkB acts as a potent oncogene that converts non-malignant epithelial cells into metastasizing tumor cells."

No Comments