Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/β-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages

Wu, Alexander T.H.; Srivastava, Prateeti; Yadav, Vijesh Kumar; Tzeng, David T.W.; Iamsaard, Sitthichai; Su, Emily Chia Yu; Hsiao, Michael; Liu, Ming Che

doi:10.1016/j.taap.2020.115109

Cited by 27 publications

(15 citation statements)

References 34 publications

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“…Exosomes secreted by TAMs transfer miR-21 to gastric cancer cells, which activates the PI3K/AKT signaling pathway and suppresses cell apoptosis to confer resistance ( Zheng et al, 2017 ). Meanwhile, TAMs can directly deliver mRNAs to enhance the expression of CDK6, mTOR, STAT3, and β-catenin, leading to cisplatin resistance in BCa cells ( Wu et al, 2020 ). In another example, exosomes released from CAFs strengthen the chemo-resistance of pancreatic cancer cells and colorectal cancer cells by activating β-catenin and the Snail pathway ( Richards et al, 2017 ; Ren et al, 2018 ).…”

Section: Tme-driven Adaptive Mechanisms Of Therapy Resistancementioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

106

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Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.

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Section: Tme-driven Adaptive Mechanisms Of Therapy Resistancementioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

106

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“…In addition to TAM recruitment, bladder tumors also influence TAM phenotype by inducing the establishment of an M2-like phenotype that will enhance tumor development in return ( Figure 1 ). Bladder tumor cells increase expression of CD206, CD163, PD-L1 and IL10 in macrophages [ 55 , 56 ] through the secretion of IL10 [ 57 ], chemokines [ 42 , 51 ], metabolic products [ 55 , 58 ], growth factors [ 37 ] and micro-RNA via exosome exchange [ 59 ]. Moreover, hypoxic areas, where TAMs are particularly concentrated in BCa [ 54 ], favor M2-like macrophages [ 60 ] through intracellular signaling and tumor-derived metabolites [ 61 , 62 ], which could contribute to the accumulation of pro-tumor macrophages in BCa.…”

Section: Macrophages In Bladder Cancermentioning

confidence: 99%

“…Macrophage count is also correlated with lymphatic metastasis underlying their role in the development of metastasis [ 29 , 35 , 65 ]. Macrophages promote lymphangiogenesis by the secretion of VEGF-C/D [ 51 , 66 ] and increase the ability of bladder tumor cells to form colonies and generate tumor spheres [ 56 , 67 ]. Macrophages further favor the development of metastasis by inducing tumor cell invasion through the production of CXCL8 and osteopontin [ 33 , 59 , 68 , 69 ].…”

Section: Macrophages In Bladder Cancermentioning

confidence: 99%

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

Leblond

Zdimerova

Desponds

et al. 2021

Cancers

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Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies are being developed and clinically tested to target these cells. Bladder cancer (BCa) is one of the most common cancers, and despite heavy treatments, including immune checkpoint inhibitors (ICIs), the overall patient survival for advanced BCa is still poor. TAMs are present in bladder tumors and play a significant role in BCa development. However, few investigations have analyzed the effect of targeting TAMs in BCa. In this review, we focus on the importance of TAMs in a cancerous bladder, their association with patient outcome and treatment efficiency as well as on how current BCa treatments impact these cells. We also report different strategies used in other cancer types to develop new immunotherapeutic strategies with the aim of improving BCa management through TAMs targeting.

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“…Four groups were established: GBM-N019 only (5 mg/kg five times/week I.P), palbociclib only (150 mg/kg five times/week, P.O), the combination of GBM-N019 and palbociclib, and the control receiving a sham injection. The body weights were monitored weekly using an electronic weighing balance while the tumor growth was monitored using IVIS 200 bioluminescence imaging system (Caliper Life Science Inc., Hopkinton, MA, USA) every week [ 64 ]. The change in tumor burden was determined by total photon flux (photons/s), which was calculated as flux per unit area and unit angle over the region of interest (ROI).…”

Section: Methodsmentioning

confidence: 99%

A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling

Huang

Wen

et al. 2021

Cells

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Glioblastoma (GBM) is one of the most aggressive brain malignancies with high incidences of developing treatment resistance, resulting in poor prognoses. Glioma stem cell (GSC)-derived exosomes are important players that contribute to GBM tumorigenesis and aggressive properties. Herein, we investigated the inhibitory roles of GBM-N019, a novel small molecule on the transfer of aggressive and invasive properties through the delivery of oncogene-loaded exosomes from GSCs to naïve and non-GSCs. Our results indicated that GBM-N019 significantly downregulated the expressions of the mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and cyclin-dependent kinase 6 (CDK6) signaling networks with concomitant inhibitory activities against viability, clonogenicity, and migratory abilities of U251 and U87MG cells. Treatments with GBM-N019 halted the exosomal transfer of protein kinase B (Akt), mTOR, p-mTOR, and Ras-related protein RAB27A to the naïve U251 and U87MG cells, and rescued the cells from invasive and stemness properties that were associated with activation of these oncogenes. GBM-N019 also synergized with and enhanced the anti-GBM activities of palbociclib in vitro and in vivo. In conclusion, our results suggested that GBM-N019 possesses good translational relevance as a potential anti-glioblastoma drug candidate worthy of consideration for clinical trials against recurrent glioblastomas.

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Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/β-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages

Cited by 27 publications

References 34 publications

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling

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