Rapid tumor recurrence in a novel murine GBM surgical model is associated with Akt/PD-L1/vimentin signaling

Liu, Feng; Xu, Xiao; Li, Chun-Yang; Zhang, Ting Ting; Yin, Song; Liu, Guo Qiang; Hu, Feng; Shang, Yu; Chen, Xiao Qian

doi:10.1016/j.bbrc.2021.06.072

Cited by 2 publications

(4 citation statements)

References 22 publications

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“…G422 TN -tumors in superficial cerebral cortex of mice were subjected to surgery or surgery combined regimen as previously described [ 13 , 14 ]. Briefly, intracranial tumor was fully exposed by removing skull cap of 5 mm-in diameter centered with the original injection site.…”

Section: Methodsmentioning

confidence: 99%

“…This model is different from others as G422 TN cells have been maintained for in vivo passaging and in high aggressiveness. We have optimized the G422 TN -GBM mouse model [ 13 , 14 ], making it faithful to recapitulate the therapeutic responses of human GBM. In this model, the standard surgery/RT/TMZ regimen or RT/TMZ are most effective but only slightly increases mouse survival time with a comparable efficacy of human GMB [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Liu

Zhou

Jiang

et al. 2023

J Exp Clin Cancer Res

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Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Conclusion Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Liu

Zhou

Jiang

et al. 2023

J Exp Clin Cancer Res

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“…Liu et al, established one orthotopic murine recurrent model of intracranial tumor mass that had macroscopically been removed and undergone chemo/radiotherapy to maximize survival benefits [41]. This experimental mimic of the therapeutic process extended the median survival and revealed the involvement of the Akt/vimentin signaling in GBM recurrence.…”

Section: Murine Models That Mimic Gbm Recurrencementioning

confidence: 99%

“…This experimental mimic of the therapeutic process extended the median survival and revealed the involvement of the Akt/vimentin signaling in GBM recurrence. Interestingly, after surgical operation, astrocytes were highly positive for GFAP protein (i.e., in an activated state) and expressed PD-L1 around the tumorinfiltrating foci and invasive front, suggesting that host astrocytes play an essential role in immunosuppression of GBM recurrence after surgery [41]. On the other hand, Zhao et al, imitated recurrence using a genetically engineered murine GBM cell model with the HSV-TK suicide gene, in which the cell death program is activated after ganciclovir administration, allowing initial tumor expansion and partial regression in the deep area of the brain [42], and then revealed the increased invasiveness of rGBM cells and a higher ratio of monocyte-derived macrophages among the entire population of tumor-associated myeloid cells.…”

Section: Murine Models That Mimic Gbm Recurrencementioning

confidence: 99%

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas

Murota

Tabu

Taga

2022

Cells

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Glioblastoma multiforme (GBM) is the most incurable tumor (due to the difficulty in complete surgical resection and the resistance to conventional chemo/radiotherapies) that displays a high relapse frequency. Cancer stem cells (CSCs) have been considered as a promising target responsible for therapy resistance and cancer recurrence. CSCs are known to organize a self-advantageous microenvironment (niche) for their maintenance and expansion. Therefore, understanding how the microenvironment is reconstructed by the remaining CSCs after conventional treatments and how it eventually causes recurrence should be essential to inhibit cancer recurrence. However, the number of studies focusing on recurrence is limited, particularly those related to tumor immune microenvironment, while numerous data have been obtained from primary resected samples. Here, we summarize recent investigations on the immune microenvironment from the viewpoint of recurrent GBM (rGBM). Based on the recurrence-associated immune cell composition reported so far, we will discuss how CSCs manipulate host immunity and create the special microenvironment for themselves to regrow. An integrated understanding of the interactions between CSCs and host immune cells at the recurrent phase will lead us to develop innovative therapies and diagnoses to achieve GBM eradication.

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Rapid tumor recurrence in a novel murine GBM surgical model is associated with Akt/PD-L1/vimentin signaling

Cited by 2 publications

References 22 publications

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas

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