Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Manini, Ivana; Caponnetto, Federica; Dalla, Emiliano; Ius, Tamara; Pepa, Giuseppe Maria Della; Pegolo, Enrico; Bartolini, Anna; Rocca, Giuseppe La; Menna, Grazia; Loreto, Carla Di; Olivi, Alessandro; Škrap, Miran; Sabatino, Giovanni; Cesselli, Daniela

doi:10.3390/cancers12102960

Cited by 24 publications

(28 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The GASCs were then maintained, in vitro, applying a previously established protocol that has been optimized for culturing multipotent adult stem cells from normal and neoplastic human tissues. 24…”

Section: Gasc Isolation and Characterizationmentioning

confidence: 99%

“…To achieve this goal, we performed a targeted sampling of 3 areas characterized by different 5-aminolevulinic acid (5-ALA) fluorescence-bright (ALA+), pale (ALA PALE), and negative (ALA−)-corresponding to the tumor mass, infiltrated peritumoral area (beyond the area of enhancement on MRI), and the healthy brain, respectively, during surgery. [20][21][22][23][24]…”

mentioning

confidence: 99%

See 1 more Smart Citation

Immunoregulatory effects of glioma-associated stem cells on the glioblastoma peritumoral microenvironment: a differential PD-L1 expression from core to periphery?

Menna

Manini

Cesselli

et al. 2022

Neurosurgical Focus

Self Cite

View full text Add to dashboard Cite

OBJECTIVE Glioma-associated stem cells (GASCs) have been indicated as possible players in supporting growth and recurrence in glioblastoma. However, their role in modulating immune response in the peritumoral area has not yet been described. In this study, the authors aimed to investigate programmed death-ligand 1 (PD-L1) differential expression at the protein level in GASCs derived from different tumor areas (core, periphery, and surrounding healthy brain). METHODS Tumor tissue samples were collected from patients who underwent surgery for a histopathologically confirmed diagnosis of glioblastoma. Sampling sites were confirmed via neuronavigation and categorized on 5-aminolevulinic acid (5-ALA) fluorescence as bright (ALA+), pale (ALA PALE), or negative (ALA−), which corresponds to the tumor mass, infiltrated peritumoral area, and healthy brain, respectively, during surgery. GASCs were first isolated from the 3 regions and analyzed; then Western blot analysis was used to evaluate the level of PD-L1 expression in the GASCs. RESULTS Overall, 7 patients were included in the study. For all patients, the mean values ± SD of PD-L1 expression in GASCs for ALA+, ALA PALE, and ALA− were 1.12 ± 1.14, 0.89 ± 0.63, and 0.57 ± 0.18, respectively. The differentially expressed values of PD-L1 in GASCs sampled from the 3 areas were found to be significant (p < 0.05) for 3 of the 7 patients: patient S470 (ALA+ vs ALA− and ALA PALE vs ALA−), patient S473 (ALA+ vs ALA PALE and ALA PALE vs ALA−), and patient S509 (ALA+ vs ALA−). CONCLUSIONS This analysis showed, for the first time, that GASCs expressed a constitutive level of PD-L1 and that PD-L1 expression in GASCs was not uniform among patients or within the same patient. GASC analysis combined with 5-ALA–guided sampling (from core to periphery) made it possible to highlight the role of the tumor microenvironment at the infiltrating margin, which might cause clinical resistance, opening interesting perspectives for the future.

show abstract

Section: Gasc Isolation and Characterizationmentioning

confidence: 99%

mentioning

confidence: 99%

Immunoregulatory effects of glioma-associated stem cells on the glioblastoma peritumoral microenvironment: a differential PD-L1 expression from core to periphery?

Menna

Manini

Cesselli

et al. 2022

Neurosurgical Focus

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the common aggressive cancers, and especially in GBM, phenotypic spatial and temporal heterogeneity, in both stem and non-stem subsets, is a dynamic process responding to treatment interventions and driven further and faster by hypoxia [30,[36][37][38][39]. GBM may be considered a collection of mutually interacting, mutually supporting cellular subpopulations demanding the use of a multi-drug combination to achieve prolonged treatment response.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Clinical Study of CUSP9v3: Nine Repurposed Drugs Combined With Temozolomide for the Treatment of Recurrent Glioblastoma

Halatsch¹,

Kast²,

Karpel‐Massler³

et al. 2021

Preprint

View full text Add to dashboard Cite

Purpose: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide - version 3 - (CUSP9v3) to address this issue. The aim of this proof-of-concept clinical trial was to assess the safety of CUSP9v3. Study Design: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. Results: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. Progression-free survival after 12 months was 50%. Conclusions: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

show abstract

“…We used 5ALA, together with intraoperative contrast enhanced ultrasound and neuronavigation that matches the criteria of central part of the tumor (CORE), periphery with still uptake of 5ALA (5ALA+) and periphery without uptake of 5ALA but still suspicious for pathology or border territory (5ALA-). With the aid of neuronavigation and 5-ALA fluorescence, three areas of sampling were defined: the core of the tumor (CUSA CORE), the 5-ALA positive (CUSA A+) and the 5-ALA negative (CUSA A-) periphery [ 62 ]. During tumor resection, CUSA was configured with the following standard setting: 50% amplitude, 50% aspiration, and 3mL/min of irrigation with normal saline solution.…”

Section: Methodsmentioning

confidence: 99%

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Rocca¹,

Simboli

Vincenzoni

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

The present investigation aimed to characterize the protein profile of cavitating ultrasound aspirator fluid of newly diagnosed and recurrent glioblastoma comparing diverse zones of collection, i.e., tumor core and tumor periphery, with the aid of 5-aminolevulinic acid fluorescence. The samples were pooled and analyzed in triplicate by LC-MS following the shotgun proteomic approach. The identified proteins were then grouped to disclose elements exclusive and common to the tumor state or tumor zones and submitted to gene ontology classification and pathway overrepresentation analysis. The proteins common to the distinct zones were further investigated by relative quantitation, following a label free approach, to disclose possible differences of expression. Nine proteins, i.e., tubulin 2B chain, CD59, far upstream element-binding, CD44, histone H1.4, caldesmon, osteopontin, tropomyosin chain and metallothionein-2, marked the core of newly diagnosed glioblastoma with respect to tumor periphery. Considering the tumor zone, including the core and the fluorescence positive periphery, the serine glycine biosynthesis, pentose phosphate, 5-hydroxytryptamine degredation, de novo purine biosynthesis and huntington disease pathways resulted statistically significantly overrepresented with respect to the human genome of reference. The fluorescence negative zone shared several protein elements with the tumor zone, possibly indicating the presence of pathological aspects of glioblastoma rather than of normal brain parenchyma. On the other hand, its exclusive protein elements were considered to represent the healthy zone and, accordingly, exhibiting no pathways overrepresentation. On the contrary to newly diagnosed glioblastoma, pathway overrepresentation was recognized only in the healthy zone of recurrent glioblastoma. The TGFβ signaling pathway, exclusively classified in the fluorescence negative periphery in newly diagnosed glioblastoma, was instead the exclusive pathway classified in the tumor core of recurrent glioblastoma. These results, preliminary obtained on sample pools, demonstrated the potential of cavitron ultrasonic surgical aspirate fluid for proteomic profiling of glioblastoma able to distinguish molecular features specific of the diverse tumor zones and tumor states, possibly contributing to the understanding of the highly infiltrative capability and recurrent rate of this aggressive brain tumor and opening to potential clinical applications to be further investigated.

show abstract

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Cited by 24 publications

References 89 publications

Immunoregulatory effects of glioma-associated stem cells on the glioblastoma peritumoral microenvironment: a differential PD-L1 expression from core to periphery?

Immunoregulatory effects of glioma-associated stem cells on the glioblastoma peritumoral microenvironment: a differential PD-L1 expression from core to periphery?

A Pilot Clinical Study of CUSP9v3: Nine Repurposed Drugs Combined With Temozolomide for the Treatment of Recurrent Glioblastoma

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Contact Info

Product

Resources

About