Novel pathway identifies rapamycin as tumor angiogenesis inhibitor

August 14, 2006

New research has uncovered a signaling pathway sufficient to induce formation of abnormal tumor-like blood vessels in otherwise healthy, normal tissues. These changes in vasculature were reversible and could be blocked by rapamycin, a compound that is currently in clinical use as an immunosuppressant and under investigation as an anticancer therapy. The findings appear in the August issue of Cancer Cell, published by Cell Press.

Compared to normal blood vessels, blood vessels associated with tumors are large, twisted, and leaky. Previous research has shown that overexpression of the cytokine VEGF-A leads to formation of tumor-like blood vessels. Dr. Laura E. Benjamin, from Beth Israel Deaconess Medical School and Harvard Medical School, and colleagues observed that tumor blood vessel cells exhibit activation of a signaling molecule, called Akt, that acts downstream of VEGF-A and has been linked to blood vessel cell survival. To investigate the function of Akt, the researchers used transgenic mice that expressed activated Akt in normal endothelial cells without the complicating influence of tumor cells.

Activation of Akt stimulated formation of abnormal blood vessels in healthy, normal tissues. The Akt-induced vessels had the same structural and functional abnormalities seen in tumor blood vessels. Simply removing or inhibiting the activated Akt was sufficient to reverse the vascular changes. Treatment with rapamycin, a compound with antiproliferative and immunosuppressive properties known to decrease Akt activation, blocked Akt-driven changes in blood vessels. Rapamycin also reduced tumor growth and abnormal vasculature in a mouse tumor model.

"Rapamycin inhibited tumor growth and tumor vascular permeability, which we hypothesize are in part due to effects of rapamycin on endothelial Akt activation. These findings indicate a possible clinical utility of rapamycin as an angiogenesis inhibitor and support a novel pathway for rapamycin action via Akt inhibition. Although more research is needed, rapamycin is an exciting novel therapy that should be further explored in cancer treatment as an antiangiogenic agent as well as an effective vascular Akt inhibitor," concludes Dr. Benjamin.
-end-
The researchers include Thuy L. Phung of the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts; Keren Ziv of the Weizmann Institute of Science in Rehovot, Israel; Donnette Dabydeen, Godfred Eyiah-Mensah, Marcela Riveros, Carole Perruzzi, Jingfang Sun and Rita A. Monahan-Earley of the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts; Ichiro Shiojima of the Whitaker Cardiovascular Institute, Boston University School of Medicine in Boston, Massachusetts; Janice A. Nagy of the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts; Michelle I. Lin of the Boyer Center for Molecular Medicine, Yale University School of Medicine in New Haven, Connecticut; Kenneth Walsh Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts; Ann M. Dvorak of the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts; David M. Briscoe of the Transplantation Research Center, Children's Hospital and Harvard Medical School in Boston, Massachusetts; Michal Neeman of the Weizmann Institute of Science in Rehovot, Israel; William C. Sessa of the Boyer Center for Molecular Medicine, Yale University School of Medicine in New Haven, Connecticut; Harold F. Dvorak and Laura E. Benjamin of the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts.

This work was supported by US Public Health Service NIH grants, the Israel Science Foundation (M.N.), and a grant from NRSA Training.

Phung et al.: "Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin." Publishing in Cancer Cell 10, 159-170, August 2006. DOI 10.1016/j.ccr.2006.07.003

Related preview by Stoeltzing et al.: "Preview: Intracellular signaling in tumor and endothelial cells: The expected and, yet again, the unexpected."

Cell Press

Related Blood Vessels Articles from Brightsurf:

Biofriendly protocells pump up blood vessels
In a new study published today in Nature Chemistry, Professor Stephen Mann and Dr Mei Li from Bristol's School of Chemistry, together with Associate Professor Jianbo Liu and colleagues at Hunan University and Central South University in China, prepared synthetic protocells coated in red blood cell fragments for use as nitric oxide generating bio-bots within blood vessels.

Specific and rapid expansion of blood vessels
Upon a heart infarct or stroke, rapid restoration of blood flow, and oxygen delivery to the hypo perfused regions is of eminent importance to prevent further damage to heart or brain.

Flexible and biodegradable electronic blood vessels
Researchers in China and Switzerland have developed electronic blood vessels that can be actively tuned to address subtle changes in the body after implantation.

Lumpy proteins stiffen blood vessels of the brain
Deposits of a protein called ''Medin'', which manifest in virtually all older adults, reduce the elasticity of blood vessels during aging and hence may be a risk factor for vascular dementia.

Cancer cells take over blood vessels to spread
In laboratory studies, Johns Hopkins Kimmel Cancer Center and Johns Hopkins University researchers observed a key step in how cancer cells may spread from a primary tumor to a distant site within the body, a process known as metastasis.

Novel function of platelets in tumor blood vessels found
Scientists at Uppsala University have discovered a hitherto unknown function of blood platelets in cancer.

Blood vessels can make you fat, and yet fit
IBS scientists have reported Angiopoietin-2 (Angpt2) as a key driver that inhibits the accumulation of potbellies by enabling the proper transport of fatty acid into general circulation in blood vessels, thus preventing insulin resistance.

Brothers in arms: The brain and its blood vessels
The brain and its surrounding blood vessels exist in a close relationship.

Feeling the pressure: How blood vessels sense their environment
Researchers from the University of Tsukuba discovered that Thbs1 is a key extracellular mediator of mechanotransduction upon mechanical stress.

Human textiles to repair blood vessels
As the leading cause of mortality worldwide, cardiovascular diseases claim over 17 million lives each year, according to World Health Organization estimates.

Read More: Blood Vessels News and Blood Vessels Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.