Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

Tan, David C. H.; Roth, Imogen; Wickremesekera, Agadha; Davis, Paul F.; Kaye, Andrew H.; Mantamadiotis, Theo; Stylli, Stanley S.; Tan, Swee T.

doi:10.20944/preprints201909.0327.v1

Cited by 14 publications

(1 citation statement)

References 68 publications

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“…This may offer a novel therapeutic approach for patients with GB [76] to potentially increase overall survival while preserving their quality of life and avoiding drug toxicities. Currently we are undertaking a drug repurposing study using a cocktail consisting of propranolol (a β-blocker), metformin (an IGF/IGFR-1 blocker), curcumin (a cathepsin B blocker), aliskiren (a renin blocker), cilazapril (an ACE inhibitor), and losartan (an ARB) to treat GB [112].…”

Section: Repurposing Drugs That Target the Rasmentioning

confidence: 99%

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

Tan

Roth

Wickremesekera

et al. 2019

Cells

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Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection and adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs can be identified by embryonic stem cell markers, express components of the renin-angiotensin system (RAS) and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB patients rarely develop distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the RAS to improve overall symptom-free survival and maintain quality of life.

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Section: Repurposing Drugs That Target the Rasmentioning

confidence: 99%

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

Tan

Roth

Wickremesekera

et al. 2019

Cells

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CTSB is a negative prognostic biomarker and therapeutic target associated with immune cells infiltration and immunosuppression in gliomas

Chen

Liu

et al. 2022

Sci Rep

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Previous researches have demonstrated the meaning of CTSB for the progress of several tumors, whereas few clues about its immunological characteristic in gliomas. Here we systematically explored its biologic features and clinical significance for gliomas. 699 glioma cases of TCGA and 325 glioma cases of CGGA were respectively included as training and validating cohorts. R software was used for data analysis and mapping. We found that CTSB was remarkably highly-expressed for HGG, IDH wild type, 1p19q non-codeletion type, MGMT promoter unmethylation type and mesenchymal gliomas. CTSB could specifically and sensitively indicate mesenchymal glioma. Upregulated CTSB was an independent hazard correlated with poor survival. CTSB-related biological processes in gliomas chiefly concentrated on immunoreaction and inflammation response. Then we proved that CTSB positively related to most inflammatory metagenes except IgG, including HCK, LCK, MHC II, STAT1 and IFN. More importantly, the levels of glioma-infiltrating immune cells were positively associated with the expression of CTSB, especially for TAMs, MDSCs and Tregs. In conclusion, CTSB is closely related to the malignant pathological subtypes, worse prognosis, immune cells infiltration and immunosuppression of gliomas, which make it a promising biomarker and potential target in the diagnosis, treatment and prognostic assessment of gliomas.

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Expression of Components of the Renin-Angiotensin System by Cancer Stem Cells in Renal Clear Cell Carcinoma

et al. 2021

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This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor 2 (AT2R). Immunofluorescence co-staining or double immunohistochemical staining of these components of the RAS with stemness-associated markers OCT4 or KLF4 was performed on two of the samples. Protein and transcript expression of these components of the RAS in six RCCC tissue samples was investigated using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, angiotensin II receptor 1 (AT1R) was investigated using RT-qPCR only. Immunohistochemical staining demonstrated expression of renin, PRR, and ACE2 in 11, 13, and 13 out of 15 RCCC samples, respectively, while AT2R was expressed in all 15 samples. ACE was detected in the endothelium of normal vasculature only. Double immunohistochemical staining demonstrated localization of ACE2, but not renin, to the KLF4+ CSCs. Immunofluorescence staining showed localization of PRR and AT2R to the OCT4+ CSCs. Western blotting confirmed protein expression of all components of the RAS except renin. RT-qPCR demonstrated transcript expression of all components of the RAS including AT1R, but not AT2R, in all six RCCC tissue samples. This study demonstrated expression of PRR, ACE2, and AT2R by the CSCs within RCCC. Further studies may lead to novel therapeutic targeting of CSCs by manipulation of the RAS in the treatment of this aggressive cancer.

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Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

Cited by 14 publications

References 68 publications

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System

CTSB is a negative prognostic biomarker and therapeutic target associated with immune cells infiltration and immunosuppression in gliomas

Expression of Components of the Renin-Angiotensin System by Cancer Stem Cells in Renal Clear Cell Carcinoma

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