Study reveals a key to blood vessel growth and possible drug target

October 14, 2007

Researchers have identified a molecular pathway that plays a critical role in the growth of blood vessels. The finding not only offers an important insight into the development of the vascular system during embryonic development but suggests a potential target for inhibiting the blood vessels that fuel cancers, diabetic eye complications and atherosclerosis, the researchers say.

The study, published online on Oct. 14 in Nature Genetics. was conducted in the zebrafish, the tiny, blue-and-silver striped denizen of India’s Ganges River and many an aquarium.

A “News and Views” commentary on the paper will run in the same issue.

“We expect this finding will offer important insights into blood vessel formation in humans,” says lead author Massimo Santoro, PhD, UCSF visiting postdoctoral fellow in the lab of senior author Didier Stainier, PhD, UCSF professor of biochemistry and biophysics. “The zebrafish has proven to be an important model for discovering molecules relevant to human disease.”

Angiogenesis, or the growth of blood vessels, is active not only during embryonic development but throughout the life of the body, providing a source of oxygenated blood to tissues damaged by wounds.

However, it is also active in a number of disease processes, including cancer. Without a blood supply, tumors cannot grow beyond the size of a small pea. Cancerous tumors release chemical signals into their environment that stimulate healthy blood vessels to sprout new vessels that then extend into the tumors. During the last decade, scientists have identified several molecules that promote angiogenesis. A drug that inhibits these molecules is now commercially available and others are being studied in clinical trials.

Scientists are also exploring strategies for stimulating the growth of new blood vessels in patients whose clogged arteries prevent a sufficient blood supply to the heart muscle.

In the current study, the UCSF team determined that two well known signaling molecules, birc2 and TNF, are crucial to the survival of endothelial cells -- which line the blood vessels and maintain the integrity of the blood vessel wall during vascular development -- in zebrafish embryos.

“The pathway these molecules make up during vascular development has not been looked at before,” says Stainier. “It offers a new target for therapeutic strategies.”

The birc2 gene belongs to a family of proteins that control the balance between cell survival and cell death (apoptosis). A cell induces apoptosis when it detects that it is irreparably damaged. The integrity of the blood vessel wall is determined by a dynamic balance between endothelial cell survival and apoptosis.

The scientists started the investigation by examining zebrafish with unusual physical characteristics and working to identify the mutated genes that were responsible for the traits.

“We began with a genetic mutant that displayed vascular hemorrhage associated with vascular defects, and soon proved that the mutant had a defective birc2 gene,” says Santoro. “Without the birc2 gene, hemorrhage and blood pooling occurred, resulting in vascular regression and cell death.”

Next, through a series of genomic analyses and biochemical studies, the team discovered the critical role of birc2 and TNF in blood vessel health in the zebrafish embryo. They showed that birc2 is needed for the formation of the tumor necrosis factor receptor complex 1, a group of proteins and peptides that activate cell survival by initiating signals. Tumor necrosis factor promotes activation of NF-kB, a protein complex transcription factor involved in the transfer of genetic information. Further tests proved the existence of a genetic link between the birc2/NF-kB pathway, and that it is critical for vascular health and endothelial cell survival.

“Studies on vascular development are important so that we can better understand the molecular basis of how endothelial cell-related pathologies such as cancer, diabetic eye complications, known as retinopathies, atherosclerosis and system lupus develop,” Santoro said. “It can also help us design new therapeutic strategies for these diseases.”

The team hopes that future researchers will investigate other avenues and alternative pathways. “Because vascular health impacts many different diseases, understanding how to genetically control endothelial cell survival and apoptosis is critical to future work in these areas,” Stainier said.

Source: University of California - San Francisco

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gdpawel
not rated yet Dec 16, 2008
Direct anti-tumor and anti-vascular effects were studied of drugs in fresh biopsy specimens of cancer patients.

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms can identify the activity of both single drugs and combinations of drugs at the level of individual patients with individual cancers. It works by measuring drug effects (real-time) upon endothelial cells which make up blood vessels.

Drugs like Avastin had striking anti-microvascular effects but minimal anti-tumor effects. Tarceva and Gleevec had mixed antitumor and anti-microvascular effects. Anti-microvascular effects of Tarceva and Iressa were equal to those of Sutent and Nexavar. Anti-microvascular additivity was observed between Avastin and other drugs on an individual basis.

Conclusions of the study had shown that Tykerb has antivascular activity superior to that of Nexavar. Avastin Tykerb may be the first clinically-exploitable antivascular drug combination. High dose, intermittent 'bolus' schedules of Tykerb to coincide with Avastin administration may be clinically advantageous, even in HER2-negative tumors.

The system utilized for the study was a functional profiling assay, which may be used to individualize anti-tumor and antivascular therapy. It can be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating microvascular cells in a variety of neoplastic and non-neoplastic conditions, for drug development, and individualized cancer treatment.

The cell-based assay can accurately sort drugs into categories of above average probability of providing clinical benefit on one hand and below average probability of providing clinical benefit on the other hand, based both on tumor response and patient survival.

The consistent and specific control of cancer will require a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness. A sufficient number of independent methods of cell killing must be employed so that it is too improbable for cancer cells to evolve that can escape death or inactivation. It must examine functional aspects of every cell in the body and must do so for a prolonged period of time.

Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process.

Functional, cell culture-based assays are vastly more informative for virtually all drugs, both as single agents and in combination with each other and with traditional cytotoxic agents, than marker-based tests, including multi-gene tests.

Literature Citation: Weisenthal, LM, Patel, N, and Rueff-Weisenthal, C. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Intern Med 264:275-287, September 2008

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