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Article ; Online: Endothelial-to-osteoblast transition in normal mouse bone development

Song-Chang Lin / Guoyu Yu / Yu-Chen Lee / Jian H. Song / Xingzhi Song / Jianhua Zhang / Theocharis Panaretakis / Christopher J. Logothetis / Yoshihiro Komatsu / Li-Yuan Yu-Lee / Guocan Wang / Sue-Hwa Lin

iScience, Vol 26, Iss 2, Pp 105994- (2023)

2023

Abstract: Summary: Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC- ...

Abstract	Summary: Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and mineralization in osteogenic medium. RNA-sequencing revealed GATA family transcription factors were upregulated in EC-OSB hybrid cells and knockdown of GATA3 inhibited BMP4-induced mineralization. Our findings support that EC-to-OSB transition occurs during normal bone development and suggest a new paradigm regarding the endothelial origin of OSBs.
Keywords	Biological sciences ; Cell biology ; Cancer ; Science ; Q
Subject code	616
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Measuring the Metabolic Evolution of Glioblastoma throughout Tumor Development, Regression, and Recurrence with Hyperpolarized Magnetic Resonance

Travis C. Salzillo / Vimbai Mawoneke / Joseph Weygand / Akaanksh Shetty / Joy Gumin / Niki M. Zacharias / Seth T. Gammon / David Piwnica-Worms / Gregory N. Fuller / Christopher J. Logothetis / Frederick F. Lang / Pratip K. Bhattacharya

Cells, Vol 10, Iss 2621, p

2021 Volume 2621

Abstract: Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI ... ...

Abstract	Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI could detect changes in tumor progression faster than conventional anatomic MRI in patient-derived glioblastoma murine models. To capture the dynamic nature of cancer metabolism, hyperpolarized MRI, NMR spectroscopy, and immunohistochemistry were performed at several time-points during tumor development, regression, and recurrence. Hyperpolarized MRI detected significant changes of metabolism throughout tumor progression whereas conventional MRI was less sensitive. This was accompanied by aberrations in amino acid and phospholipid lipid metabolism and MCT1 expression. Hyperpolarized MRI can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.
Keywords	magnetic resonance imaging ; hyperpolarization ; nuclear magnetic resonance ; glioblastoma ; metabolism ; radiation therapy ; Biology (General) ; QH301-705.5
Subject code	610 ; 570
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients

Junfeng Xu / Wen-Shin Chang / Chia-Wen Tsai / Da-Tian Bau / Yifan Xu / John W. Davis / Timothy C. Thompson / Christopher J. Logothetis / Jian Gu

EBioMedicine, Vol 52, Iss , Pp - (2020)

2020

Abstract: Background: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa). Methods: We measured relative LTL in a ... ...

Abstract	Background: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa). Methods: We measured relative LTL in a cohort of 1,889 white PCa patients who were treated and followed up at the University of Texas MD Anderson Cancer Center and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after active treatments (radical prostatectomy and radiotherapy). We further used a Mendelian randomization (MR) approach to compute a weighted genetic risk score (GRS) predictive of LTL using 10 established LTL-associated genetic variants and determined whether this GRS is associated with aggressive PCa. Findings: LTL was significantly shorter in patients with higher Gleason scores at diagnosis. Dichotomized at the median value of LTL, patients with short LTL exhibited a 2.74-fold (95% confidence interval, 1.79–4.18, P = 3.11 × 10−6) increased risk of presenting with GS≥8 disease than those with long LTL in multivariate logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.53, 95% confidence interval, 1.01–2.34) compared to longer LTL in localized patients receiving prostatectomy or radiotherapy with a significant dose-response association (P for trend = 0.017) in multivariate Cox proportional hazards regression analysis. In MR analysis, genetically predicted short LTL was also associated with an increased risk of BCR (HR=1.73, 95% CI, 1.08–2.78). Interpretation: Our results showed for the first time that LTL was shorter in PCa patients with high Gleason scores and that short LTL and genetically predicted short LTL are associated with worse prognosis in PCa patients receiving prostatectomy or radiotherapy. Funding: Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP140556), National Cancer Institute Specialized Program of Research Excellence ...
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4

Guoyu Yu / Pengfei Shen / Yu-Chen Lee / Jing Pan / Jian H. Song / Tianhong Pan / Song-Chang Lin / Xin Liang / Guocan Wang / Theocharis Panaretakis / Christopher J. Logothetis / Gary E. Gallick / Li-Yuan Yu-Lee / Sue-Hwa Lin

iScience, Vol 24, Iss 4, Pp 102388- (2021)

2021

Abstract: Summary: Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal ... ...

Abstract	Summary: Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal reprogramming supports prostate cancer progression. We delineate signaling pathways mediating EC-to-OSB transition using EC lines 2H11 and SVR. We found that BMP4-activated pSmad1-Notch-Hey1 pathway inhibits EC migration and tube formation. BMP4-activated GSK3β-βcatenin-Slug pathway stimulates Osx expression. In addition, pSmad1-regulated Dlx2 converges with the Smad1 and β-catenin pathways to stimulate osteocalcin expression. By co-expressing Osx, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization in the absence of BMP4. In human prostate cancer bone metastasis specimens and MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.
Keywords	Molecular Biology ; Cell Biology ; Cancer ; Science ; Q
Subject code	570
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Cell Reports, Vol 39, Iss 1, Pp 110595- (2022)

2022

Abstract: Summary: Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate ... ...

Abstract	Summary: Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
Keywords	CP: Cancer ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Assessing Therapeutic Efficacy in Real-time by Hyperpolarized Magnetic Resonance Metabolic Imaging

Prasanta Dutta / Travis C. Salzillo / Shivanand Pudakalakatti / Seth T. Gammon / Benny A. Kaipparettu / Florencia McAllister / Shawn Wagner / Daniel E. Frigo / Christopher J. Logothetis / Niki M. Zacharias / Pratip K. Bhattacharya

Cells, Vol 8, Iss 4, p

2019 Volume 340

Abstract: Precisely measuring tumor-associated alterations in metabolism clinically will enable the efficient assessment of therapeutic responses. Advances in imaging technologies can exploit the differences in cancer-associated cell metabolism as compared to ... ...

Abstract	Precisely measuring tumor-associated alterations in metabolism clinically will enable the efficient assessment of therapeutic responses. Advances in imaging technologies can exploit the differences in cancer-associated cell metabolism as compared to normal tissue metabolism, linking changes in target metabolism to therapeutic efficacy. Metabolic imaging by Positron Emission Tomography (PET) employing 2-fluoro-deoxy-glucose ([ 18 F]FDG) has been used as a routine diagnostic tool in the clinic. Recently developed hyperpolarized Magnetic Resonance (HP-MR), which radically increases the sensitivity of conventional MRI, has created a renewed interest in functional and metabolic imaging. The successful translation of this technique to the clinic was achieved recently with measurements of 13 C-pyruvate metabolism. Here, we review the potential clinical roles for metabolic imaging with hyperpolarized MRI as applied in assessing therapeutic intervention in different cancer systems.
Keywords	cancer metabolism ; hyperpolarization ; MRI ; therapy monitoring ; metabolic imaging ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modified Logistic Regression Models Using Gene Coexpression and Clinical Features to Predict Prostate Cancer Progression

Hongya Zhao / Christopher J. Logothetis / Ivan P. Gorlov / Jia Zeng / Jianguo Dai

Computational and Mathematical Methods in Medicine, Vol

2013 Volume 2013

Abstract: Predicting disease progression is one of the most challenging problems in prostate cancer research. Adding gene expression data to prediction models that are based on clinical features has been proposed to improve accuracy. In the current study, we ... ...

Abstract	Predicting disease progression is one of the most challenging problems in prostate cancer research. Adding gene expression data to prediction models that are based on clinical features has been proposed to improve accuracy. In the current study, we applied a logistic regression (LR) model combining clinical features and gene co-expression data to improve the accuracy of the prediction of prostate cancer progression. The top-scoring pair (TSP) method was used to select genes for the model. The proposed models not only preserved the basic properties of the TSP algorithm but also incorporated the clinical features into the prognostic models. Based on the statistical inference with the iterative cross validation, we demonstrated that prediction LR models that included genes selected by the TSP method provided better predictions of prostate cancer progression than those using clinical variables only and/or those that included genes selected by the one-gene-at-a-time approach. Thus, we conclude that TSP selection is a useful tool for feature (and/or gene) selection to use in prognostic models and our model also provides an alternative for predicting prostate cancer progression.
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Building a statistical model for predicting cancer genes.

Ivan P Gorlov / Christopher J Logothetis / Shenying Fang / Olga Y Gorlova / Christopher Amos

PLoS ONE, Vol 7, Iss 11, p e

2012 Volume 49175

Abstract: More than 400 cancer genes have been identified in the human genome. The list is not yet complete. Statistical models predicting cancer genes may help with identification of novel cancer gene candidates. We used known prostate cancer (PCa) genes ( ... ...

Abstract	More than 400 cancer genes have been identified in the human genome. The list is not yet complete. Statistical models predicting cancer genes may help with identification of novel cancer gene candidates. We used known prostate cancer (PCa) genes (identified through KnowledgeNet) as a training set to build a binary logistic regression model identifying PCa genes. Internal and external validation of the model was conducted using a validation set (also from KnowledgeNet), permutations, and external data on genes with recurrent prostate tumor mutations. We evaluated a set of 33 gene characteristics as predictors. Sixteen of the original 33 predictors were significant in the model. We found that a typical PCa gene is a prostate-specific transcription factor, kinase, or phosphatase with high interindividual variance of the expression level in adjacent normal prostate tissue and differential expression between normal prostate tissue and primary tumor. PCa genes are likely to have an antiapoptotic effect and to play a role in cell proliferation, angiogenesis, and cell adhesion. Their proteins are likely to be ubiquitinated or sumoylated but not acetylated. A number of novel PCa candidates have been proposed. Functional annotations of novel candidates identified antiapoptosis, regulation of cell proliferation, positive regulation of kinase activity, positive regulation of transferase activity, angiogenesis, positive regulation of cell division, and cell adhesion as top functions. We provide the list of the top 200 predicted PCa genes, which can be used as candidates for experimental validation. The model may be modified to predict genes for other cancer sites.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: GWAS meets microarray

Ivan P Gorlov / Gary E Gallick / Olga Y Gorlova / Christopher Amos / Christopher J Logothetis

PLoS ONE, Vol 4, Iss 8, p e

are the results of genome-wide association studies and gene-expression profiling consistent? Prostate cancer as an example.

2009 Volume 6511

Abstract: Genome-wide association studies (GWASs) and global profiling of gene expression (microarrays) are two major technological breakthroughs that allow hypothesis-free identification of candidate genes associated with tumorigenesis. It is not obvious whether ... ...

Abstract	Genome-wide association studies (GWASs) and global profiling of gene expression (microarrays) are two major technological breakthroughs that allow hypothesis-free identification of candidate genes associated with tumorigenesis. It is not obvious whether there is a consistency between the candidate genes identified by GWAS (GWAS genes) and those identified by profiling gene expression (microarray genes).We used the Cancer Genetic Markers Susceptibility database to retrieve single nucleotide polymorphisms from candidate genes for prostate cancer. In addition, we conducted a large meta-analysis of gene expression data in normal prostate and prostate tumor tissue. We identified 13,905 genes that were interrogated by both GWASs and microarrays. On the basis of P values from GWASs, we selected 1,649 most significantly associated genes for functional annotation by the Database for Annotation, Visualization and Integrated Discovery. We also conducted functional annotation analysis using same number of the top genes identified in the meta-analysis of the gene expression data. We found that genes involved in cell adhesion were overrepresented among both the GWAS and microarray genes.We conclude that the results of these analyses suggest that combining GWAS and microarray data would be a more effective approach than analyzing individual datasets and can help to refine the identification of candidate genes and functions associated with tumor development.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2009-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers

Omar Alhalabi / Jianfeng Chen / Yuxue Zhang / Yang Lu / Qi Wang / Sumankalai Ramachandran / Rebecca Slack Tidwell / Guangchun Han / Xinmiao Yan / Jieru Meng / Ruiping Wang / Anh G. Hoang / Wei-Lien Wang / Jian Song / Lidia Lopez / Alex Andreev-Drakhlin / Arlene Siefker-Radtke / Xinqiao Zhang / William F. Benedict /

Amishi Y. Shah / Jennifer Wang / Pavlos Msaouel / Miao Zhang / Charles C. Guo / Bogdan Czerniak / Carmen Behrens / Luisa Soto / Vassiliki Papadimitrakopoulou / Jeff Lewis / Waree Rinsurongkawong / Vadeerat Rinsurongkawong / Jack Lee / Jack Roth / Stephen Swisher / Ignacio Wistuba / John Heymach / Jing Wang / Matthew T. Campbell / Eleni Efstathiou / Mark Titus / Christopher J. Logothetis / Thai H. Ho / Jianjun Zhang / Linghua Wang / Jianjun Gao

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when ... ...

Abstract	The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
Keywords	Science ; Q
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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