Genomic alteration can reshape tumor microenvironment to drive tumor malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that PTEN deficiency induces a symbiotic glioma-M2 macrophage interaction to support glioma progression. Mechanistically, PTEN -deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives macrophage M2 polarization by activating its receptor Tim-3 and downstream pathways in macrophages. These macrophages, in turn, secrete VEGFA to stimulate angiogenesis and support glioma growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome in glioma patients. In GBM models, blockade of Gal-9/Tim-3 signaling inhibits macrophage M2 polarization and suppresses tumor growth. Moreover, α-lactose attenuates glioma angiogenesis by down-regulating macrophage-derived VEGFA, providing a novel antivascularization strategy. Therefore, our study suggests that blockade of Gal-9/Tim-3 signaling is effective to impair glioma progression by inhibiting macrophage M2 polarization, specifically for PTEN -null GBM.

The standard protocol of treatment for glioma currently involves maximal surgical resection while maintaining neurological function. Thus, accurately and promptly delineating the glioma’s margins during microsurgery is crucial. This is to ensure minimal residual tumor tissue and avoid excessive removal, which can result in neurological impairments. The conventional and widely practiced method in neurosurgery is the use of frozen pathology. However, due to the significant time and effort this process demands, quick identification is not feasible, especially when there is a large remaining cavity requiring multiple site samplings. In the past few decades, there has been considerable advancement in surgical technology for identifying tumor boundaries. Systems like DiveScope, such as endoscopic Raman spectroscopy, multiphoton endomicroscopy, and confocal endomicroscopy, have shown significant progress. In this chapter, we aim to review the historical development and future potential of handheld pathology microscopes in neurosurgical microsurgery.

Background: Glioblastoma (GBM) is the most malignant brain tumor, with a cellular hierarchy dominated by glioma stem cells (GSCs). Understanding global communications among GSCs and other cells helps us identify potential new therapeutic targets. In this study, multi-transcriptomic analysis was utilized to explore the communication pattern of GSCs in GBM. Methods: CellChat was used to quantitatively infer and analyze intercellular communication networks from GBM single-cell RNA-sequencing (scRNA-seq) data. Gene set enrichment analysis (GSEA) was conducted to identify specific biological pathways (epithelial–mesenchymal transition, EMT) involved in the communication pattern of GSCs. Spatial transcriptomic database was used to support the relationship between EMT and GSC proliferation. Single-sample GSEA (ssGSEA) was employed to assess which GSC state exhibited the strongest association with the EMT signature. Results: The cell communication pattern of GSCs is mostly related to EMT. Multiple EMT-related genes are highly expressed in GBM, particularly in GSCs, which are associated with poor prognosis. In addition, EMT-related genes are most enriched in mesenchymal-like (MES-like) GSCs. Tumor patients with MES-like GSC-enriched signatures demonstrate the most unfavorable prognosis compared to those harboring proneural-like (PN-like) or classical-like (CL-like) GSCs. Conclusions: This study suggests that GSCs facilitate GBM progression through intercellular communication in the pattern of EMT. EMT-associated genes may drive the differentiation of GSCs toward a MES-like phenotype, thereby leading to poorer clinical outcomes. Consequently, targeting EMT-related pathways could represent a novel therapeutic strategy for GBM treatment.

Rapidly and accurately identifying glioma margins during neurosurgery has significance in reducing the recurrence rate and improving perioperative safety. The purpose of our study is to assess the clinical performance of the DiveScope, a novel handheld histopathologic microscope in rapidly differentiating glioma from normal brain tissue during neurosurgery. Prior to the application of the DiveScope to neurosurgery, we first dissected 3 experimental pigs' brains and observed them under the DiveScope in vivo. Subsequently, 32 ex-vivo specimens from 18 patients were included in the present study. The excised suspicious tissue was sequentially stained with sodium fluorescein and methylene blue and scanned with DiveScope during surgery. The adjacent tissue was sent to the department of pathology for frozen section examination. They would eventually be sent to the pathology department later for hematoxylin and eosin (HE) staining for final confirmation. The positive likelihood ratio (PLR), negative likelihood ratio (NLR), sensitivity, specificity, and area under the curve (AUC) of the device were calculated. In addition, we compared the difference in time consumption between DiveScope and frozen sections for the initial judgment. We also provided a typical case to elucidate the clinical application of the DiveScope in neurosurgery. When HE-stained sections were used as the gold standard, the sensitivity and the specificity of the DiveScope was 88.29% (95% CI: 70.8% − 97.6%) and 100% (95% CI: 39.8% − 100.0%), respectively. In contrast, the sensitivity and specificity of the frozen sections were 100% (95% CI: 87.7% − 100%) and 75% (95% CI: 19.4% − 99.4%), respectively. The AUC of the DiveScope and the frozen sections were 0.946 and 0.875 respectively, with no statistical difference(P = 0.578). Concerning time consumption, in tumorous samples with ≥ 0.8 cm in diameter, the Divescope cost 10.7 minutes on average while frozen pathology cost 41.9 minutes (p < 0.0001). For tumor samples < 0.8 cm in diameter, DiveScope cost an average of 10.7 minutes while the frozen pathology cost 50.1 minutes (p < 0.01). Compared with traditional pathologic examination of frozen sections, DiveScope was faster and displayed an equal accuracy for judging tumor margins intraoperatively.

Indian Journal of Ophthalmology - Case Reports, All India Ophthalmological Society