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Circulating Tumor Cells Seen in Subset of Glioblastoma Multiforme Brain Cancer Cases

NEW YORK (GenomeWeb) – A study published online today in Science Translational Medicine suggests the brain cancer glioblastoma multiforme (GBM) can shed cells that make their way into a patient's blood stream, arguing against the notion that the disease is mainly restricted to the central nervous system.

German and Austrian researchers used immunostaining methods to search for GBM cells in blood samples from 141 individuals affected by GBM. The technique turned up apparent circulating tumors cells in more than one-fifth of patients with the central nervous system cancer, with subsequent comparative genomic hybridization, fluorescence in situ hybridization, and targeted gene sequencing experiments linking such cells back to individuals' brain tumors.

Tumor cell migration into the bloodstream did not appear to depend on whether the GBM case considered was recurrent or whether the tumor tissue was disturbed by surgical intervention, the study authors noted. They argued that the findings may provide new clues for not only managing and tracking GBM, but also for whether individuals with the disease can safely donate organs to others.

"Checking the status of metastasis beyond the central nervous system might be indicated for GBM patients who are long-term survivors," the study's senior authors Klaus Pantel and Sabine Riethdorf, both with the University Medical Center Hamburg-Eppendorf's tumor biology department, and their colleagues wrote, "and GBM patients without CTCs might be considered as transplant donors."

"The CTC detection approach developed in this study is easily applicable as a companion diagnostic to identify patients with extracranial tumor spread," they added, "and it might be advisable to exclude these patients as organ donors."

Metastasis occurs only infrequently in GBM cases, prompting the belief that the cells from the tumors are largely confined to the central nervous system and unlikely to travel to other parts of the body. That assumption has been called into question recently, though, with reports of metastatic GBM developing in some individuals who received organ donations from individuals with the disease.

The possibility that GBM tumor cells move out of the central nervous system has implications for GBM patients as well, authors of the new analysis explained, since these errant cells could cause theoretically lead to delayed metastasis in GBM survivors who are living longer with improved treatments.

In an effort to understand if and when GBM cells might move through patients' blood, the researchers assessed 147 blood samples from 141 individuals with grade IV GBM. The group included several individuals who were experiencing their first or second recurrence of the disease.

After enriching for mononuclear white blood cells, the team attempted to track down CTCs in the samples using antibodies that target a glial fibrillary acidic protein. The immunocytochemical approach uncovered that GBM marker protein in blood samples from 29 of the 141 patients tested.

The presence or absence of CTCs did not appear to be related to whether individuals were experiencing recurrent disease or not. Likewise, the team detected similar CTC patterns regardless of whether blood samples were collected before, during, or after tumor resection surgery.

When the researchers used CGH and FISH to characterize the apparent CTCs, they found genomic alterations that coincided with their suspected GBM tumor source, including EGFR amplifications and recurrent gains or losses involving stretches of chromosomes 7 or 10.

To further shore up ties to the GBM tumors, the team did targeted sequencing on two of the primary tumor samples, focusing on 370 genes previously implicated in cancer. There, it verified that selected somatic mutations from those samples were subsequently identified in corresponding CTCs from the same individuals.

A lone glial fibrillary acidic protein-positive cell turned up in blood samples from 28 unaffected controls, including almost two-dozen cancer-free individuals and five patients with other types of cancer that had metastasized to the brain.

Together, the results support the idea that the roaming cells detected in the first stage of the study represented authentic CTCs originating from GBM tumors, according to the study's authors, who argued that their GBM CTC assay approach may help in identifying GBM patients at risk of metastasis and in screening potential organ donors.