Glioblastoma remains one of the most feared diagnoses in medicine, and one of its standard treatments has long carried a frustrating paradox. Bevacizumab, a monoclonal antibody that blocks vascular endothelial growth factor (VEGF), can dramatically shrink these tumors by starving them of their blood supply. Yet the benefit is almost always temporary. Tumors that melt away on scans tend to return in a more diffuse, invasive form that no longer depends on new blood vessels to grow. A new study published in the Journal of Neuro-Oncology offers what may be the clearest molecular explanation yet for this escape act, pointing to a single protein, Annexin A2 (ANXA2), as both a marker and a possible driver of the shift from angiogenic growth to infiltrative invasion.
The research, led by Taketo Ezaki and colleagues at Keio University, The Jikei University School of Medicine, and collaborating institutions across Japan, analyzed 66 tissue specimens from 33 glioblastoma patients. What makes the work exceptional is its longitudinal design. Japan is the only country where bevacizumab is approved for use at initial diagnosis, which allowed the team to collect neoadjuvant bevacizumab (neoBev) specimens—tumors removed after patients had already received the drug before surgery. The cohort included 15 bevacizumab-naive cases and 18 neoBev cases, alongside 33 refractory specimens gathered from salvage surgery and autopsy. Crucially, the refractory group included paired samples from the same patients at different treatment phases, enabling direct molecular comparison between the bevacizumab-responsive and bevacizumab-resistant states of individual tumors.
The team measured ANXA2 expression using quantitative real-time PCR on formalin-fixed paraffin-embedded tissue, normalizing against the housekeeping genes GAPDH and beta-actin and applying the comparative cycle threshold method. Protein localization was mapped with immunohistochemistry and triple-label immunofluorescence, staining for ANXA2 alongside the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) and the stem cell marker CD133. The statistical centerpiece was a multivariate Cox proportional hazards model that adjusted for age, the number of temozolomide and bevacizumab cycles, extent of resection, and sex. Against this rigorous backdrop, one finding stood out with unusual clarity: high ANXA2 mRNA expression was an independent predictor of both shorter progression-free survival (hazard ratio 2.85, p = 0.028) and shorter overall survival (hazard ratio 3.12, p = 0.015).
The survival data became even more compelling when patients were stratified by both treatment and expression level. Within the neoBev group, patients with low ANXA2 expression achieved significantly longer progression-free survival than those with high expression (p = 0.034), and the same held true for overall survival (p = 0.004). In fact, the clinical benefit of neoadjuvant bevacizumab appeared to be restricted almost entirely to the low-ANXA2 subgroup. Among low-expressers, those treated with neoBev showed significantly longer progression-free survival than naive counterparts (p = 0.006). By contrast, the neoBev high-expression group fared significantly worse in overall survival than the naive high-expression group (p = 0.029), suggesting that elevated ANXA2 does not merely fail to respond to the drug—it actively counteracts its efficacy.
Why would this one protein carry such prognostic weight? The answer lies in its unusual dual role in tumor biology. ANXA2 sits upstream of the plasmin-MMP axis: it facilitates the activation of plasminogen, which in turn triggers matrix metalloproteinases MMP2 and MMP9, enzymes that degrade the extracellular matrix and clear the path for tumor invasion. At the same time, ANXA2 is deeply involved in angiogenesis, the very process bevacizumab is designed to suppress. It also participates in stemness, epithelial-mesenchymal transition, and hypoxia signaling. Unlike MMP2, MMP9, TIMP-1, or PAI-1, which each reflect a single component of matrix remodeling, ANXA2 functions as a hub connecting multiple invasion-related pathways, making it a potentially more reliable readout of the angiogenic-to-invasive transition that defines bevacizumab resistance.
The spatial analyses added a striking layer of biological detail. Immunohistochemistry revealed intense ANXA2 expression in the tumor vasculature and stroma at the glioblastoma leading edge—the invasive frontier where tumor cells fan out into surrounding brain tissue. Triple-label immunofluorescence showed ANXA2 co-localizing with HIF-1α, the master transcriptional regulator of the hypoxic response. This is mechanistically coherent: bevacizumab-induced vascular pruning creates hypoxic niches, and HIF-1α directly upregulates ANXA2 through a hypoxia-responsive element. ANXA2 can in turn stabilize HIF-1α, creating a positive feedback loop that sustains tumor progression under oxygen starvation. The team also found that ANXA2 activates STAT3 signaling, and the ANXA2-STAT3-oncostatin M receptor axis has previously been shown to drive the mesenchymal, highly invasive phenotypic changes characteristic of resistant glioblastoma.
One apparent paradox in the data deserves attention. When the researchers correlated ANXA2 expression with the cumulative number of bevacizumab cycles across the whole cohort, they found a significant negative relationship (Spearman’s r = −0.456, p = 0.009): more drug exposure was associated with lower ANXA2 expression, and patients receiving 11 to 20 cycles showed significantly reduced expression compared with those receiving 10 or fewer. The authors interpret this as a form of survivor bias. Patients who derive sustained benefit from bevacizumab continue receiving it for many cycles while maintaining low ANXA2 levels, whereas a subset of tumors with intrinsically high ANXA2 activity never respond well in the first place. In other words, the absolute ANXA2 level after drug exposure, rather than the population-wide trend, is what best reflects biological resistance and clinical outcome. Tumors that fail to suppress ANXA2 despite treatment appear predisposed to infiltrative escape and early resistance.
The study also probed whether conventional imaging could capture this biology, and the answer was largely no. Recurrence patterns on MRI—classified as contrast-enhancing T1 flare-up, T2 diffuse infiltration, or T2 circumscribed lesions—did not differ significantly in ANXA2 expression between treatment groups. Furthermore, radiological response assessed with the modified RANO 2.0 criteria, which incorporate both contrast-enhancing and FLAIR features, did not correlate significantly with survival. This dissociation between radiology and molecular pathology suggests that ANXA2-driven invasive adaptation operates below the resolution of standard imaging criteria, which are influenced by vascular density, blood-brain barrier integrity, edema, and other factors that obscure the underlying cellular behavior. A molecular biomarker may therefore detect resistance earlier and more faithfully than any scan.
The authors are candid about the limitations. The study was retrospective and not randomized, the sample size was modest, molecular profiling under the current WHO CNS5 classification—including IDH mutation status and MGMT promoter methylation—was not uniformly available, and the immunohistochemical analyses were qualitative rather than quantitatively scored. No functional validation experiments, such as ANXA2 knockdown in cell models, were performed, and the number of salvage surgical specimens was limited. The overall survival benefit of neoadjuvant bevacizumab itself requires further validation, and exploratory subgroup comparisons did not all retain statistical significance after correction for multiple comparisons. These caveats temper but do not erase the central signal, which survived multivariate adjustment and was consistent across paired, unpaired, imaging, and histological analyses.
Even so, the implications are substantial. If validated prospectively, ANXA2 could serve a dual clinical role: a predictive biomarker identifying which newly diagnosed patients will genuinely benefit from bevacizumab, and a therapeutic target whose suppression might prevent the infiltrative escape that currently undermines anti-angiogenic therapy. An ANXA2-guided strategy, in which biopsy-based expression testing directs treatment selection, would represent a meaningful step toward personalized neuro-oncology in a disease where treatment options remain desperately scarce. Recent work showing that lactylation-driven, USP4-mediated stabilization of ANXA2 maintains glioblastoma stem cells and radioresistance further suggests that drugging this pathway could attack multiple resistance mechanisms at once. For a tumor that has defeated nearly every therapeutic advance of the past two decades, a single protein that explains both prognosis and treatment failure is a lead worth chasing.
Subject of Research: Annexin A2 expression as a biomarker of bevacizumab resistance and infiltrative escape in glioblastoma
Article Title: Annexin A2 associated with bevacizumab resistance and infiltrative escape in glioblastoma
Article References: Annexin A2 associated with bevacizumab resistance and infiltrative escape in glioblastoma. (n.d.). https://doi.org/10.1007/s11060-026-05772-4
Image Credits: AI Generated
DOI: 10.1007/s11060-026-05772-4
Keywords: glioblastoma, Annexin A2, bevacizumab, drug resistance, biomarker, angiogenesis, tumor invasion, HIF-1alpha, hypoxia, neoadjuvant therapy, prognosis, neuro-oncology
Cite Scienmag News
APA MLA Chicago
Nathaniel Bowman. (October 3, 2026). Brain Tumor Protein Reveals Why a Common Cancer Drug Stops Working. Scienmag. https://scienmag.com/brain-tumor-protein-reveals-why-a-common-cancer-drug-stops-working/
Nathaniel Bowman. “Brain Tumor Protein Reveals Why a Common Cancer Drug Stops Working.” Scienmag, 3 October 2026, https://scienmag.com/brain-tumor-protein-reveals-why-a-common-cancer-drug-stops-working/. Accessed 3 October 2026.
Nathaniel Bowman. “Brain Tumor Protein Reveals Why a Common Cancer Drug Stops Working.” Scienmag. October 3, 2026. https://scienmag.com/brain-tumor-protein-reveals-why-a-common-cancer-drug-stops-working/
Copy citation Download RIS
Tags: angiogenesisAnnexin A2Annexin A2 protein in brain tumorsanti-angiogenic therapy in brain cancerbevacizumabbevacizumab resistance mechanismsbiomarkerdrug resistanceGlioblastomaglioblastoma treatment challengesHIF-1alphahypoxialongitudinal analysis of glioblastomamolecular drivers of tumor recurrencemolecular markers of glioblastoma progressionneoadjuvant therapyneuro-oncologyprognosistumor blood supply deprivationtumor invasiontumor invasion and infiltration in glioblastomatumor microenvironment changes after therapyVEGF pathway in brain tumors
