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Interestingly, and adding to evidence that glioblastoma is a systemic rather than local disease, the marrows of the skull and femur reacted differently to the cancer. Credit: Neuroscience News<\/p>\nSummary: Glioblastoma, the most lethal brain cancer, doesn\u2019t just damage the brain\u2014it erodes the skull and disrupts the immune system by reshaping marrow inside the skull. Researchers discovered that tumors increase skull-to-brain channels, allowing waves of inflammatory immune cells to flow to the cancer site, fueling its growth.<\/p>\n
Tests in mice and patients revealed skull thinning unique to glioblastoma and immune imbalances that rendered therapies less effective. The findings highlight the urgent need to design treatments that address glioblastoma as a systemic disease rather than a purely local brain tumor.<\/p>\n
Key Facts:<\/p>\n
Skull Erosion: Glioblastoma causes bone loss in the skull, particularly at sutures.Immune Hijacking: Tumors shift skull marrow toward pro-inflammatory cells, fueling aggressiveness.Treatment Challenges: Anti-osteoporosis drugs stopped bone erosion but sometimes worsened tumor progression and blocked immunotherapy benefits.<\/p>\n
Source: Albert Einstein College of Medicine<\/p>\n
Scientists at\u00a0Montefiore Einstein Comprehensive Cancer Center\u00a0(MECCC) and\u00a0Albert Einstein College of Medicine\u00a0have shown for the first time that glioblastoma\u2014the deadliest form of brain cancer\u2014affects not just the brain but also erodes the skull, alters the makeup of skull marrow, and interferes with the body\u2019s immune response.<\/p>\n
Drugs intended to inhibit skull-bone loss made the cancer more aggressive, according to results published today in\u00a0Nature Neuroscience.<\/p>\n
Interestingly, and adding to evidence that glioblastoma is a systemic rather than local disease, the marrows of the skull and femur reacted differently to the cancer. Credit: Neuroscience News<\/p>\n
\u201cOur discovery that this notoriously hard-to-treat brain cancer interacts with the body\u2019s immune system may help explain why current therapies\u2014all of them dealing with glioblastoma as a local disease\u2014have failed, and it will hopefully lead to better treatment strategies,\u201d said the paper\u2019s corresponding author\u00a0Jinan Behnan, Ph.D., assistant professor in the\u00a0Leo M. Davidoff Department of Neurological Surgery\u00a0and in the department of\u00a0microbiology & immunology\u00a0at Einstein, and a member of the National Cancer Institute (NCI)-designated MECCC.<\/p>\n
According to the NCI, approximately 15,000 people are diagnosed with glioblastoma each year. The median survival of those who receive standard treatment of surgery, chemotherapy, and radiation is approximately 15 months.<\/p>\n
A Matter of Marrow<\/p>\n
As is true for many other bones, the skull contains marrow in which immune cells and other blood cells form. Dr. Behnan\u2019s research on glioblastoma and the skull was prompted by recent studies revealing extremely thin channels that connect the skull with its underlying brain, allowing molecules and cells to travel between the skull\u2019s marrow and the brain.<\/p>\n
Dr. Behnan and colleagues used advanced imaging techniques on mice that developed two different types of glioblastomas. They found that the tumors caused skull bones to erode, especially along the sutures where skull bones fuse.<\/p>\n
Such erosions seem to be unique to glioblastoma and other malignant intracranial tumors, since they don\u2019t occur with strokes, other types of brain damage, or even other systemic cancers. Computerized-tomography (CT) images of patients with glioblastoma revealed that decreases in skull thickness were present in the same anatomic areas as in mice.<\/p>\n
The skull erosions in the mice were found to have increased the number and diameter of the skull-to-bone channels. The researchers hypothesized that these channels might allow the glioblastoma to transmit signals to the skull marrow that could profoundly change its immune landscape.<\/p>\n
A Tilt Towards Inflammation
Using single-cell RNA sequencing, the researchers found that glioblastoma had dramatically shifted the skull marrow\u2019s immune-cell balance in favor of pro-inflammatory myeloid cells\u2014nearly doubling the levels of inflammatory neutrophils, while nearly eliminating several types of antibody-producing B cells as well as other B cells.<\/p>\n
\u201cThe skull-to-brain channels allow an influx of these numerous pro-inflammatory cells from the skull marrow to the tumor, rendering the glioblastoma increasingly aggressive and, all too often, untreatable,\u201d said study co-author\u00a0E. Richard Stanley, Ph.D.,\u00a0professor of\u00a0developmental and molecular biology\u00a0at Einstein.<\/p>\n
\u201cThis indicates the need for treatments that restore the normal balance of immune cells in the skull marrow of people with glioblastoma. One strategy would be suppressing the production of pro-inflammatory neutrophils and monocytes while at the same time restoring the production of T and B cells.\u201d<\/p>\n
Interestingly, and adding to evidence that glioblastoma is a systemic rather than local disease, the marrows of the skull and femur reacted differently to the cancer. Glioblastoma activated several genes in the skull marrow that boosted production of inflammatory immune cells; but in femur marrow, the cancer suppressed genes needed to produce several types of immune cells.<\/p>\n
The researchers wondered if administering anti-osteoporosis drugs that prevent bone loss would affect skull-bone erosion, glioblastoma, or both. To find out, they gave mice with glioblastoma tumors two different drugs approved by the U.S. Food and Drug Administration for treating osteoporosis.<\/p>\n
Both drugs (zoledronic acid and denosumab) halted skull erosion\u2014but one of them (zoledronic acid) also fueled tumor progression in one type of glioblastoma. Both drugs also blocked the beneficial effects of anti-PD-L1, an immunotherapy drug that boosts levels of tumor-fighting T cells.<\/p>\n
The\u00a0Nature Neuroscience\u00a0paper is titled \u201cBrain Tumors Induce Widespread disruption of Calvarial Bone and Alteration of Skull Marrow Immune Landscape.\u201d Additional MECCC and Einstein authors include Abhishek Dubey, Biljana Stangeland, Imane Abbas, David Fooksman, Ph.D., Wade R. Koba, B.S., Jinghang Zhang, M.D., Benjamin T. Himes, Ph.D., Derek Huffman, Ph.D., Zhiping Wu, Rachel Welch, David Reynolds, B.S., Kostantin Dobrenis, Ph.D., Qinge Ye, Kevin Fisher, and Emad Eskandar, M.D. Other authors include Erika Yamashita, Yutaka Uchida and Masaru Ishii, at Osaka University, Osaka, Japan, Robert A. Harris at Karolinska Hospital Solna, Stockholm, Sweden, Gregory M Palmer at Duke University Medical Center, Durham, North Carolina, Olivia R. Lu and Winson S. Ho at University of California, San Francisco, CA, and Alexander F. Fiedler at German Rheumatism Research Center (DRFZ) and Freie Universit\u00e4t Berlin, Berlin, Germany.<\/p>\n
Key Questions AnsweredQ: How does glioblastoma affect more than just the brain?<\/p>\n
A: The cancer erodes skull bones, alters skull marrow, and disrupts immune balance.<\/p>\n
Q: What immune changes occur in the skull marrow in glioblastoma brain cancer?<\/p>\n
A: Glioblastoma nearly doubles pro-inflammatory neutrophils while eliminating many B cells, worsening tumor aggression.<\/p>\n
Q: Why might current treatments for glioblastoma fail?<\/p>\n
A: Standard therapies treat glioblastoma as a local disease, but the study shows it acts systemically, affecting skull-bone and immune interactions.<\/p>\n
About this glioblastoma brain cancer research news<\/p>\n
Author: Elaine Iandoli<\/a>
Source: Albert Einstein College of Medicine<\/a>
Contact: Elaine Iandoli \u2013 Albert Einstein College of Medicine
Image: The image is credited to Neuroscience News<\/p>\n