Can Angiogenesis Unlock Mysteries of Glioblastoma? A Report from 3 Investigative Fronts

Progress in our understanding of the role of angiogenesis — the process of new blood vessel formation — in the growth and spread of glioblastoma tumors is hard to keep up with these days. And many of the new insights are emerging from projects underway at Cleveland Clinic’s Lerner Research Institute.

“We are gaining a deep understanding of how glioblastomas form new blood vessels on both the molecular and cellular levels,” says Candece Gladson, MD, of the Lerner Research Institute’s Department of Cancer Biology and Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center. “Discovering the keys to angiogenesis offers hope of improving therapies against this aggressive brain cancer, as well as against other tumors.”

Dr. Gladson recently shared status reports on three of the multiple projects she oversees focusing on angiogenesis in glioblastoma. Her observations are recapped below.

1) Effects of bevacizumab on cancer cells in the perivascular space

Bevacizumab, a humanized monoclonal antibody against VEGF (a signal protein that stimulates blood vessel formation), is a standard treatment for patients with recurrent glioblastoma. Dr. Gladson’s laboratory has recently characterized in detail what happens as bevacizumab is internalized and processed in cancer stem cells residing near blood vessels. According to Dr. Gladson, understanding how the medication is “trafficked” through cellular processes inside the cell — i.e., whether it is quickly destroyed by the cell or recycled to keep functioning as a therapeutic agent — may be critical to how well a patient responds to the therapy.

“We have found a mechanism by which tumor cells can degrade bevacizumab, making the therapy ineffective for some patients,” she explains. “This understanding can lead to ways to identify patients who may have enhanced degradation before bevacizumab treatment is started so that an alternative therapy can be chosen.”

The team’s findings were recently published in Clinical Cancer Research (2017 Sep 14 [Epub ahead of print]).

Dr. Gladson notes that understanding the cellular effects of bevacizumab has implications well beyond glioblastoma therapy, as the agent is also used to treat renal cancer as well as metastatic colon and lung cancers.

2) Characterizing endothelial cells in glioblastomas vs normal brain

Dr. Gladson’s group has also found important differences between the endothelial cells of glioblastomas and those from healthy brain tissue. Such differences may hold clues to what drives angiogenesis in tumors — and may even offer new targets for cancer therapies.

The group recently published a paper in the Journal of Neuro-oncology (2017;131:449-458) focused on the receptors for tumor necrosis factor (TNF), a signaling protein associated with processes leading to cell death or survival. They reported their discovery that elevated blood levels of a soluble receptor for this factor, known as sTNF-R1, are associated with reduced survival in patients with recurrent glioblastoma.

The team further found that blood concentrations of sTNF-R1 reflect its level of expression on endothelial cells from the tumor biopsy. They concluded that the receptor is overexpressed on glioblastoma endothelial cells and then cleaved off in large numbers to enter the bloodstream.

“sTNF-R1 may be a mechanism by which tumor cells can remodel their immediate surroundings and also act on distant sites within the brain and elsewhere,” explains Dr. Gladson. “These findings may lead to new blood markers predicting survival for patients with recurrent glioblastoma and other tumors driven by blood vessel formation.”

3) Investigating the perivascular niche

The microenvironment surrounding blood vessels holds important clues to angiogenesis, Dr. Gladson notes, and offers a fruitful area for research of glioblastomas. Her team has discovered that cancer cells in direct contact with blood vessels stimulate a pro-angiogenic signaling pathway in endothelial cells that promotes the migration of endothelial cells and enhances new blood vessel formation. They published their findings last year in Oncotarget (2016;7:43852-43867).

Likely implications beyond brain tumors

Dr. Gladson credits her lab’s productivity to a team approach that involves collaborations with expert researchers in the field within Cleveland Clinic and from a variety of other institutions. She also notes that her group’s findings are strengthened by their use of both in vitro cell culture methods and multiple in vivo mouse models of glioblastoma.

But most important may be her lab’s focus on an area of cancer research with broad implications. “By advancing basic understanding of glioblastomas, we are setting the stage for developing new strategies to fight many cancers that rely heavily on angiogenesis for their survival,” Dr. Gladson observes. “We expect our findings may lead to novel treatments that could change the course of cancer therapy.”