HSP47 Promotes Glioblastoma Stemlike Cell Survival by Modulating Tumor Microenvironment Extracellular Matrix through TGF-β Pathway

Jiang, Xiaochun; Zhou, Taofeng; Wang, Zhichun; Qi, Bin; Xia, Hongping

doi:10.1021/acschemneuro.6b00253

Cited by 46 publications

(40 citation statements)

References 24 publications

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“…Although many other proteins have been found to contribute to GBM tumor growth, for this review, we will focus on targets that have been discovered through proteomic approaches and TCGA data mining. Some examples of proteins overexpressed in GBM that may represent novel drug targets that were not discovered via proteomic approaches include heat-shock protein 47 ( Jiang et al, 2017b ), cathepsin L ( Xiong et al, 2017 ), glycoprotein nonmetastatic melanoma protein B ( Ono et al, 2016 ), transcription factor 12 ( Godoy et al, 2016 ), targeting protein for Xenopus kinesin-like protein 2 ( Gu et al, 2016 ), and B-cell CLL/lymphoma 3 (BCL3) ( Wu et al, 2016 ). Due to the characteristic intratumoral heterogeneity of GBM, it is likely that a single target approach will not be effective, and appropriate drug combinations will be necessary.…”

Section: Characteristics Of Protein Expression In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and “druggable” targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.

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Section: Characteristics Of Protein Expression In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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“…HSP47 is crucial during pro-collagen biosynthesis and plays and important role in the secretion of decorin, fibromodulin and lumican for the assembly of the extracellular matrix 82 . In primary grade IV gioblastoma multiforme (GBM) primary cells, an over-expression of HSP47 promoted the expression of extracellular matrix (ECM)-related genes such as COL4A2 and MMP9 83 . In fact, a reduced expression of MMP9 mRNA was reported in younger children (less than 1 year old) and older than 1 year after propranolol treatment 84 , however MMP9 did not show up in our integrative approach.…”

Section: Serpinh1mentioning

confidence: 99%

Identification of putative biomarkers for Infantile Hemangiomas and Propranolol treatment via data integration

Gómez-Acevedo

Dai²,

Strub

et al. 2020

Sci Rep

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Infantile hemangiomas (IHs) are the most common benign tumors in early childhood. They show a distinctive mechanism of tumor growth in which a rapid proliferative phase is followed by a regression phase (involution). Propranolol is an approved treatment for IHs, but its mechanism of action remains unclear. We integrated and harmonized microRNA and mRNA transcriptome data from newly generated microarray data on IHs with publicly available data on toxicological transcriptomics from propranolol exposure, and with microRNA data from IHs and propranolol exposure. We identified subsets of putative biomarkers for proliferation and involution as well as a small set of putative biomarkers for propranolol's mechanism of action for IHs, namely EPAS1, LASP1, SLC25A23, MYO1B, and ALDH1A1. Based on our integrative data approach and confirmatory experiments, we concluded that hypoxia in IHs is regulated by EPAS1 (HIF-2α) instead of HIF-1α, and also that propranolol-induced apoptosis in endothelial cells may occur via mitochondrial stress. Infantile hemangiomas (IHs) are the most common benign tumor of the vascular endothelium in infants and are present in 4 to 10% of children younger than 12 months 1,2. They manifest in any part of the body but around 60% of the cases arise in the head and neck 3. IHs have a unique growth pattern that is divided into three phases: proliferation, quiescence and involution 4. Despite the fact that the majority of IHs involute completely by 7 years of age, their hyper-proliferation can cause significant functional and disfiguring consequences and morbidities such as ulceration, bleeding, and pain. It is estimated that up to 40% of the lesions will require either surgical or medical intervention 3,5. Histologically, IHs in the proliferative phase show a lack of organization of blood vessels with densely packed capillaries composed of immature endothelial cells surrounded by pericytes, whereas during involution the capillaries are replaced with fatty and fibrous tissue 6. These findings suggest that the proliferation phase is orchestrated by angiogenesis or growth factors that lead to high mitotic rates. Among such markers reported in the literature are vascular endothelial growth factor A (VEGF-A) 7 , basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), type IV collagenase 8 , and insulin-like growth factor 2 (IGF-2) 9. On the other hand, during the involution phase there is a high expression of antiangiogenic factors (e.g., tissue inhibitor of metalloproteinase TIMP1) 8 and increasing apoptosis of endothelial cells 10. However, high expression of growth factors in both the proliferating and involution phases (e.g. bFGF) makes it difficult to clearly identify causative factors for IHs' development. From the clinical perspective, it is important to find biomarkers that robustly differentiate between proliferation and involution phases on IHs, with the hope that those biomarkers will guide medical decisions towards optimal treatments. Propranolol is a non-selective β-adre...

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“…4,5 Understanding which factors promote stemness and treatment resistance of glioma cells is of intense interest in developing new therapies in glioma. A large number of studies over the past decade have established that there is considerable plasticity in glioblastoma cell phenotypes, [6][7][8][9][10][11] that stem cell characteristics can be acquired by non-stem-like cells, 8,9,[12][13][14][15] and that microenvironmental cues such as hypoxia, 16 extracellular matrix proteins, [17][18][19][20][21][22][23][24][25] or growth factors secreted by stromal cells [26][27][28] may be sufficient to induce tumor cell stemness and therapeutic resistance. The role of the microenvironment in regulating tumor stemness is further supported by the finding that stem-like tumor cells are enriched in specific tumor niches; in GBM, primarily the perivascular niche (PVN) and hypoxic compartments.…”

Section: Introductionmentioning

confidence: 99%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance; however, little is known about how the microenvironment responds to radiation. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 inhibitors abrogated glioma stemness induced by irradiated astrocytes. TGM2 inhibition reduced survival of glioma cells in in vitro and ex vivo tumor models.These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy in glioma.

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HSP47 Promotes Glioblastoma Stemlike Cell Survival by Modulating Tumor Microenvironment Extracellular Matrix through TGF-β Pathway

Cited by 46 publications

References 24 publications

Current Challenges and Opportunities in Treating Glioblastoma

Current Challenges and Opportunities in Treating Glioblastoma

Identification of putative biomarkers for Infantile Hemangiomas and Propranolol treatment via data integration

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

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