Glioma subtypes determine how the dangerous tumors spread, evade anti-angiogenic treatment

April 27, 2018

A multi-institutional research team has identified a new mechanism by which the dangerous brain tumors called gliomas develop resistance to anti-angiogenic treatment. The team's report, published online in Cancer Cell, describes finding how different molecular subtypes of glioma cells use different strategies to spread through the brain and how anti-angiogenic treatment selects for a treatment-resistant cellular subtype.

"Despite massive basic and clinical research efforts, the treatment of glioblastoma and other malignant gliomas remains one of the most challenging tasks in clinical oncology," says Rakesh Jain, PhD, director of the Edwin L. Steele Laboratories for Tumor Biology in the Massachusetts General Hospital (MGH) Department of Radiation Oncology and co-senior author of the report. "Glioblastomas are highly vascularized and interact closely with pre-existing blood vessels for oxygen and nutrients. They also contain a very diverse population of cells, with characteristics of stem cell and other cells found within the brain, and may use different strategies to recruit or access blood vessels, depending on the local microenvironment and on treatments that are applied."

Previous studies have revealed several ways that gliomas can migrate within the brain - including "co-option" in which single cells migrate along blood vessels or as dense clusters that lead to the formation of new blood vessels. To investigate mechanisms underlying these two strategies, the research team, primarily comprised of investigators from MGH and the University of California San Francisco (https://www.ucsf.edu/) (USCF), focused on a protein called Olig2, normally involved in the development of brain cells called oligodendrocytes and expressed in most glioma subtypes.

Oligodendrocyte precursors (OPCs) that express Olig2 can act as glioma progenitors; and within OPCs, signaling controlled by a protein called Wnt7 is known to play a role in embryonic vascular development within the brain, including the cells' migration along blood vessels. The team's series of experiments revealed the following:

"We have discovered how Wnt signaling drives the process of single-cell, vascular co-option in gliomas, a mechanism that is strongly induced by anti-angiogenic treatment," says Jain, the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School.
-end-
Co-senior author David Rowich, MD, PhD, ScD, of UCSF and the University of Cambridge in the U.K., adds, "These findings have significant therapeutic implications for our understanding of heterogeneity in glioma and how tumor components exploit alternative strategies to interact successfully with the vasculature despite anti-angiogenic treatment. Our identification of the Olig2/Wnt7 vessel co-option pathway reveals a potential target for future combination therapies."

The co-lead authors are Amelie Griveau, PhD, UCSF, and Giorgio Seano, PhD, Steele Labs, MGH Radiation Oncology. Support for the study includes SPORE grants P50 CA097257 and P50 CA165962, and grants R35 CA197743 and P01 CA080124 from the National Cancer Institute; grants from the Bryan's Dream Foundation, Pediatric Brain Tumor Foundation, Loglio Foundation, Howard Hughes Medical Institute, the Wellcome Trust, the National Foundation for Cancer Research and the Harvard Ludwig Cancer Center.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service and returned to the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

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.