Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma

Fianco, Giulia; Mongiardi, Maria Patrizia; Levi, Andrea; Luca, Teresa De; Desideri, Marianna; Trisciuoglio, Daniela; Bufalo, Donatella Del; Cinà, Irene; Benedetto, Anna Di; Mottolese, Marcella; Gentile, Antonietta; Centonze, Diego; Ferré, Fabrizio; Barilá, Daniela

doi:10.7554/elife.22593

Cited by 58 publications

(53 citation statements)

References 32 publications

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“…Similarly, drug-resistant ovarian cancer cells can also secrete more CCL2 and blocking CCL2 increased sensitivity of ovarian cancer cells to chemotherapeutic drugs 16 . Enhanced the expression and secretion of CCL2 also lead to neovascularization and increased resistance to chemotherapy in glioblastoma 43 . Indeed, we succeeded in detecting increased level of CCL2 in cancer patients before surgical tumor removal.…”

Section: Discussionmentioning

confidence: 99%

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer

Xu¹,

Qi²,

Han³

et al. 2018

Int. J. Biol. Sci.

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Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells. Such secreted CCL2 could not only maintain chemoresistance in drug-resistant cancer cells but also confer drug resistance to drug-sensitive cancer cells. CCL2 attenuated drug-induced cytotoxicity by activating PI3K-Akt-mTOR signaling to inhibit proapoptotic autophagy and increase SQSTM1 expression. CCL2 expression in primary carcinoma tissues also correlated well with SQSTM1 expression. Either CCL2 knock-down or autophagy induction successfully reversed drug resistance of tumor cells. Moreover, increased expression of SQSTM1 in turn activated CCL2 transcription via NF-κB signal pathway, representing a positive feedback loop to maintain drug resistance. Therefore, our results provided a new insight to understand drug resistance, and indicated the potential value of CCL2 as a biomarker and intervention target for chemotherapy resistance.

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Section: Discussionmentioning

confidence: 99%

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer

Xu¹,

Qi²,

Han³

et al. 2018

Int. J. Biol. Sci.

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“…Modulation of caspase-8 may affect chemotherapy sensitivity not only by interfering with the apoptotic response, but also by additional pathways. Negative regulation of caspase-8 in GBM may trigger resistance to apoptosis, correlates with a reduction in the level of expression of inflammatory cytokines, resulting in increased sensitivity to TMZ via a yet unknown molecular pathway (Fianco et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The expression of Caspase-8 in GBM is often withdrawn, and is upregulated in a mesenchymal group (Verhaak et al, 2010;Stupack, 2013). But the silencing of Caspase-8 can sensitize the cancer cells with the use of the TMZ in the treatment (Fianco et al, 2016;Fianco et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Research Article Expression of microRNAs miR-126 and miR-873 and genes CASPASE-8 and C-FLIP in neurospheres of Glioblastoma lines U-343 subjected to treatment with ionizing radiation and temozolomide.

Pansani¹,

Turra²,

Neto³

et al. 2019

Genet. Mol. Res.

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Glioblastoma is considered incurable, even with a combination of therapies (chemo and radiotherapy), and surgical resection. New therapeutic approaches are needed to improve the prognosis of patients with glioblastoma. In recent decades, research has focused on molecular biology of brain tumors. We examined the role of programmed cell death, apoptosis, through two microRNAs that act as possible pro and anti-apoptotic gene regulators. We evaluated the expression of the genes CASPASE-8 and C-FLIP and microRNAs miR-126-5p and miR-873-5p in adhered cells (AC) and neurospheres (NS) from cell line U343, which were submitted to temozolomide (TMZ) and ionizing radiation (IR), isolated and associated (TMZ + IR). We concluded that microRNA-126 and 873 were differentially expressed as as a function of treatment regime in glioblastomas. The higher expression of the caspase-8 gene in adhered cells in the group treated with IR when compared to the other groups at time 48 h suggests that the ionizing radiation in the adhered cells of the glioblastoma cell line culture has apoptosis-inducing properties.

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“…Finally, Fianco et al [ 20 ], using in vitro and in vivo glioblastoma models, highlighted the link between inflammation, angiogenesis and chemoresistance. The authors showed that in an inflammatory microenvironment, Caspase 8, a protein implicated in apoptosis, promotes NF-κB transcription factor activation with consequent increase of VEGF, IL-6, IL-8, IL-1β and MCP-1 secretion, enhancing neovascularization and resistance to temozolomide (TMZ), an alkylating agent widely used in glioblastoma treatment.…”

Section: Chemoresistance Due To Changes In Tmementioning

confidence: 99%

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

Ros

Gregorio

Iorio

et al. 2018

IJMS

170

130

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For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.

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Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma

Cited by 58 publications

References 32 publications

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer

Research Article Expression of microRNAs miR-126 and miR-873 and genes CASPASE-8 and C-FLIP in neurospheres of Glioblastoma lines U-343 subjected to treatment with ionizing radiation and temozolomide.

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

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