Brain Cancer Treatment Using Genetic Material from Bone Marrow Cells

In a first-of-its-kind experiment using microvesicles generated from mesenchymal bone marrow cells (MSCs) to treat cancer, neurological researchers at Henry Ford Hospital have discovered a novel approach for treatment of tumors.

Specifically, the research team found that introducing genetic material produced by MSCs significantly reduced a particularly resistant form of malignant brain tumor in living lab rats.

“This is the first foray of its type in experimental cancer therapy, and it represents a highly novel and potentially effective treatment,” says Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute and vice chairman of the Department of Neurology at Henry Ford Hospital.

The research is published in the current issue Cancer Letters.

“I think this is an important and very novel approach for the treatment of cancers, and in this particular case the treatment of glioma,” says Dr. Chopp. “We have been at the forefront of developing microRNAs as a means to treat disease, such as cancer and neurological injury.

“This study shows it is effective in the living brain, and may even lend itself to specific cancer therapy, customized for the individual patient,” Chopp adds.

Chopp and his colleagues focused their efforts on glioma, by far the most common type of malignant brain tumor and one with a notably poor prognosis for survival.

Tumor cells were surgically implanted in the brains of anesthetized male lab rats and allowed to grow for five days.

The tumors then were injected with exosomes containing molecules of a microRNA called miR-146b – found in earlier Henry Ford research to have a strong effect on glioma cells.

Exosomes are microscopic “lipid bubbles” that once were thought to carry and get rid of “old” proteins that were no longer needed by the body. After they were more recently found to also carry RNA, whole new fields of study were suggested, including groundbreaking work by Henry Ford researchers.

In the rat study, Dr. Chopp and his colleagues used MSC bone marrow cells to produce the exosomes containing the miR-146b they injected into the cancerous tumors.

Five days after this treatment, the rats were euthanized and their brains were removed, prepared for study and examined. Tumor size was measured using computer software.

“We found that one injection of exosomes containing miR-146b five days after tumor implantation led to a significant reduction in tumor volume at 10 days after implant,” Chopp says. “Our data suggest that miR-146b elicits an anti-tumor effect in the rat brain, and that MSCs can be used as a ‘factory’ to generate exosomes genetically altered to contain miR-146b to effectively treat tumor.”

(Image: iStock)

Blood marrow derived cells regulate appetite

Bone marrow cells that produce brain-derived eurotrophic factor (BDNF), known to affect regulation of food intake, travel to part of the hypothalamus in the brain where they “fine-tune” appetite, said researchers from Baylor College of Medicine and Shiga University of Medical Science in Otsu, Shiga, Japan, in a report that appears online in the journal Nature Communications.

"We knew that blood cells produced BDNF," said Dr. Lawrence Chan, professor of molecular and cellular biology and professor and chief of the division of diabetes, endocrinology & metabolism in the department of medicine and director of the federally funded Diabetes Research Center, all at BCM. The factor is produced in the brain and in nerve cells as well. "We didn’t know why it was produced in blood cells."

Fluorescent marker reveals surprise

Dr. Hiroshi Urabe and Dr. Hideto Kojima, current and former postdoctoral fellows in Chan’s laboratory respectively, looked for BDNF in the brains of mice who had not been fed for about 24 hours. The bone marrow-derived cells had been marked with a fluorescent protein that showed up on microscopy. To their surprise, they found cells producing BDNF in a part of the brain’s hypothalamus called the paraventricular nucleus.

"We knew that in embryonic development, some blood cells do go to the brain and become microglial cells," said Chan. (Microglial cells form part of the supporting structure of the central nervous system. They are characterized by a nucleus from which "branches" expand in all directions.) "This is the first time we have shown that this happens in adulthood. Blood cells can go to one part of the brain and become physically changed to become microglial-like cells."

However, these bone marrow cells produce a bone marrow-specific variant of BDNF, one that is different from that produced by the regular microglial cells already in the hypothalamus.

Only a few of these blood-derived cells actually reach the hypothalamus, said Chan.

"It’s not very impressive if you look casually under the microscope," he said. However, a careful scrutiny showed that the branching nature of these cells allow them to come into contact with a whole host of brain cells.

"Their effects are amplified," said Chan.

Curbing the urge

Mice that are born lacking the ability to produce blood cells that make BDNF overeat, become obese and develop insulin resistance (a lack of response to insulin that affects the ability to metabolize glucose). A bone marrow transplant that restores the gene for making the cells that produce BDNF can normalize appetite, said Chan. However, a transplant of bone marrow that does not contain this gene does not reverse overeating, obesity or insulin resistance.

When normal bone marrow cells that produce BDNF are injected into the third ventricle (a fluid-filled cavity in the brain) of mice that lack BDNF, they no longer have the urge to overeat, said Chan.

All in all, the studies represent a new mechanism by which these bone-marrow derived cells control feeding through BDNF and could provide a new avenue to attack obesity, said Chan.

He and his colleagues hypothesize that the bone marrow cells that produce BDNF fine tune the appetite response, although a host of different appetite-controlling hormones produced by the regular nerve cells in the hypothalamus do the lion’s share of the work.

"Bone marrow cells are so accessible," said Chan. “If these cells play a regulatory role, we could draw some blood, modify something in it or add something that binds to blood cells and give it back. We may even be able to deliver medication that goes to the brain," crossing the blood-brain barrier. Even a few of these cells can have an effect because their geometry means that they have contact with many different neurons or nerve cells.