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  1. Article ; Online: Keeping a track on leptomeningeal disease in non-small cell lung cancer: A single-institution experience with CNSide

    Puri, Sonam / Malani, Rachna / Chalmers, Anna / Kerrigan, Kathleen / Patel, Shiven B / Monynahan, Kelly / Cannon, Laura / Blouw, Barbara / Akerley, Wallace

    Neuro-oncology advances

    2023  Volume 6, Issue 1, Page(s) vdad150

    Abstract: Background: Leptomeningeal disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) ... ...

    Abstract Background: Leptomeningeal disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) diagnostic modalities, including cerebrospinal fluid (CSF) cytology, MRI, and clinical evaluation. These hindrances contribute to the poor survival of LMD patients. CNSide is a CLIA-validated test that detects and characterizes CSF-derived tumor cells and cell-free (cf) DNA. We performed a retrospective analysis on the utility of CNSide to analyze CSF obtained from advanced non-small cell lung cancer (aNSCLC) patients with suspected LMD treated at the Huntsman Cancer Institute in Salt Lake City, UT.
    Methods: CNSide was used to evaluate CSF from 15 patients with aNSCLC. CSF tumor cell quantification was performed throughout treatment for 5 patients. CSF tumor cells and cfDNA were characterized for actionable mutations.
    Results: In LMD-positive patients, CNSide detected CSF tumor cells in 88% (22/25) samples versus 40% (10/25) for cytology (matched samples). CSF tumor cell numbers tracked response to therapy in 5 patients where CNSide was used to quantify tumor cells throughout treatment. In 75% (9/12) of the patients, genetic alterations were detected in CSF, with the majority representing gene mutations and amplifications with therapeutic potential. The median survival for LMD patients was 16.1 m (5.2-NR).
    Conclusions: We show that CNSide can supplement the management of LMD in conjunction with SOC methods for the diagnosis, monitoring response to therapy, and identifying actionable mutations unique to the CSF in patients with LMD.
    Language English
    Publishing date 2023-12-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 3009682-0
    ISSN 2632-2498 ; 2632-2498
    ISSN (online) 2632-2498
    ISSN 2632-2498
    DOI 10.1093/noajnl/vdad150
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

    Barbour, Andrew B / Blouw, Barbara / Taylor, Lynne P / Graber, Jerome J / McGranahan, Tresa / Blau, Molly / Halasz, Lia M / Lo, Simon S / Tseng, Yolanda D / Venur, Vyshak / Yang, Jonathan T

    Journal of neuro-oncology

    2024  

    Abstract: Purpose: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells ( ... ...

    Abstract Purpose: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors.
    Methods: We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival.
    Results: Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively.
    Conclusions: CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.
    Language English
    Publishing date 2024-03-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 604875-4
    ISSN 1573-7373 ; 0167-594X
    ISSN (online) 1573-7373
    ISSN 0167-594X
    DOI 10.1007/s11060-024-04615-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Investigating the contribution of hyaluronan to the breast tumour microenvironment using multiparametric MRI and MR elastography.

    Reeves, Emma L / Li, Jin / Zormpas-Petridis, Konstantinos / Boult, Jessica K R / Sullivan, James / Cummings, Craig / Blouw, Barbara / Kang, David / Sinkus, Ralph / Bamber, Jeffrey C / Jamin, Yann / Robinson, Simon P

    Molecular oncology

    2023  Volume 17, Issue 6, Page(s) 1076–1092

    Abstract: Hyaluronan (HA) is a key component of the dense extracellular matrix in breast cancer, and its accumulation is associated with poor prognosis and metastasis. Pegvorhyaluronidase alfa (PEGPH20) enzymatically degrades HA and can enhance drug delivery and ... ...

    Abstract Hyaluronan (HA) is a key component of the dense extracellular matrix in breast cancer, and its accumulation is associated with poor prognosis and metastasis. Pegvorhyaluronidase alfa (PEGPH20) enzymatically degrades HA and can enhance drug delivery and treatment response in preclinical tumour models. Clinical development of stromal-targeted therapies would be accelerated by imaging biomarkers that inform on therapeutic efficacy in vivo. Here, PEGPH20 response was assessed by multiparametric magnetic resonance imaging (MRI) in three orthotopic breast tumour models. Treatment of 4T1/HAS3 tumours, the model with the highest HA accumulation, reduced T
    MeSH term(s) Humans ; Female ; Multiparametric Magnetic Resonance Imaging ; Hyaluronic Acid/metabolism ; Tumor Microenvironment ; Elasticity Imaging Techniques ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/drug therapy ; Magnetic Resonance Imaging/methods
    Chemical Substances Hyaluronic Acid (9004-61-9)
    Language English
    Publishing date 2023-05-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2415106-3
    ISSN 1878-0261 ; 1574-7891
    ISSN (online) 1878-0261
    ISSN 1574-7891
    DOI 10.1002/1878-0261.13437
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: A Preclinical Investigation into the Effects of Aging on Dermal Hyaluronan Properties and Reconstitution Following Recombinant Human Hyaluronidase PH20 Administration.

    Connor, Robert J / Blouw, Barbara / Cowell, Jessica / Chen, Kelly / Zhao, Chunmei / Kang, David W

    Dermatology and therapy

    2020  Volume 10, Issue 3, Page(s) 503–513

    Abstract: Introduction: There is currently no consensus in the literature concerning the impact of aging on the properties of hyaluronan (HA) in the subcutaneous (SC) space. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates SC administration of injected ... ...

    Abstract Introduction: There is currently no consensus in the literature concerning the impact of aging on the properties of hyaluronan (HA) in the subcutaneous (SC) space. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates SC administration of injected therapeutics by depolymerizing SC HA, facilitating bulk fluid flow, dispersion and absorption. This study assessed the impact of intrinsic aging on HA in the SC space and thus the ability of rHuPH20 to enhance delivery of co-administered therapeutics.
    Methods: Histologic evaluations of HA levels and degradation were performed on human skin samples from six age groups, aged from 20 to 100 years. HA levels were evaluated by HA staining and degradation by staining samples for HA following incubation with rHuPH20. HA was extracted from samples and HA size determined by gel electrophoresis. Dermal reconstitution was assessed in young (aged 1.5 months) and elderly (aged > 16 months) mice. Baseline dye dispersion was measured at 5 and 20 min post-intradermal dye injection. Following treatment with rHuPH20, dye dispersion was measured again at 2, 24, 48, 72 and 96 h.
    Results: Distribution of HA was confined to the interstitial space between adipocytes, with similar pericellular presence and levels of HA found across all age groups. Substantial levels of high-molecular-weight HA were observed in all age groups at baseline. Incubation with a clinically relevant dose of rHuPH20 resulted in degradation of all SC HA and similar degradation profiles independent of age. No difference in dye dispersion time was observed between young and elderly mice across the range of time points assessed, with dye dispersion returning to baseline levels by 24 h after rHuPH20 treatment.
    Conclusions: Subcutaneous delivery of approved therapeutics facilitated by co-administration with rHuPH20 should not be impacted by intrinsic aging, with this study providing no evidence for an effect of aging on HA distribution, structure or a loss of rHuPH20 efficacy.
    Language English
    Publishing date 2020-05-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2680284-3
    ISSN 2190-9172 ; 2193-8210
    ISSN (online) 2190-9172
    ISSN 2193-8210
    DOI 10.1007/s13555-020-00380-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy.

    Clift, Renee / Souratha, Jennifer / Garrovillo, Sheryl A / Zimmerman, Susan / Blouw, Barbara

    Cancer research

    2019  Volume 79, Issue 16, Page(s) 4149–4159

    Abstract: Immunotherapies targeting immune checkpoint inhibitors have changed the landscape of cancer treatment, however, many patients are resistant or refractory to immunotherapy. The sensitivity of tumor cells to immunotherapy may be influenced by hyaluronan ( ... ...

    Abstract Immunotherapies targeting immune checkpoint inhibitors have changed the landscape of cancer treatment, however, many patients are resistant or refractory to immunotherapy. The sensitivity of tumor cells to immunotherapy may be influenced by hyaluronan (HA) accumulation in the tumor microenvironment (TME). Enzymatic degradation of HA by pegvorhyaluronidase alfa (PEGPH20; PVHA) remodels the TME. This leads to reduced tumor interstitial pressure and decompressed tumor blood vessels, which are both associated with increased exposure of tumor cells to chemotherapy drugs. Here, we demonstrate PVHA increased the uptake of anti-programmed death-ligand 1 (PD-L1) antibody in HA-accumulating animal models of breast cancer. The increased levels of anti-PD-L1 antibody were associated with increased accumulation of T cells and natural killer cells and decreased myeloid-derived suppressor cells. PD-L1 blockade significantly inhibited tumor growth when combined with PVHA, but not alone. Our results suggest that PVHA can sensitize HA-accumulating tumors to anti-PD-L1 immunotherapy. SIGNIFICANCE: These findings show removal of hyaluronan in the tumor microenvironment improves immune cells and checkpoint inhibitors access to tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4149/F1.large.jpg.
    MeSH term(s) Animals ; Antibodies, Monoclonal/pharmacology ; B7-H1 Antigen/antagonists & inhibitors ; B7-H1 Antigen/immunology ; Drug Resistance, Neoplasm/drug effects ; Female ; Hyaluronic Acid/metabolism ; Hyaluronoglucosaminidase/metabolism ; Hyaluronoglucosaminidase/pharmacology ; Immunotherapy/methods ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/pathology ; Mammary Neoplasms, Experimental/pathology ; Mammary Neoplasms, Experimental/therapy ; Mice, Inbred BALB C ; T-Lymphocytes/drug effects ; T-Lymphocytes/pathology ; Tumor Microenvironment/drug effects
    Chemical Substances Antibodies, Monoclonal ; B7-H1 Antigen ; Cd274 protein, mouse ; Hyaluronic Acid (9004-61-9) ; Hyaluronoglucosaminidase (EC 3.2.1.35) ; PEGPH20 (EC 3.2.1.35)
    Language English
    Publishing date 2019-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-18-3060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models.

    Morosi, Lavinia / Meroni, Marina / Ubezio, Paolo / Fuso Nerini, Ilaria / Minoli, Lucia / Porcu, Luca / Panini, Nicolò / Colombo, Marika / Blouw, Barbara / Kang, David W / Davoli, Enrico / Zucchetti, Massimo / D'Incalci, Maurizio / Frapolli, Roberta

    Journal of experimental & clinical cancer research : CR

    2021  Volume 40, Issue 1, Page(s) 286

    Abstract: Background: Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood ...

    Abstract Background: Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs.
    Methods: We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry.
    Results: Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model.
    Conclusion: Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.
    MeSH term(s) Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Antineoplastic Agents, Phytogenic/therapeutic use ; Female ; Humans ; Hyaluronoglucosaminidase/pharmacology ; Hyaluronoglucosaminidase/therapeutic use ; Mice ; Neoplasms/drug therapy ; Paclitaxel/pharmacology ; Paclitaxel/therapeutic use ; Tumor Microenvironment ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents, Phytogenic ; Hyaluronoglucosaminidase (EC 3.2.1.35) ; PEGPH20 (EC 3.2.1.35) ; Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2021-09-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-021-02070-x
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  7. Article ; Online: Dynamic Contrast-enhanced MRI Detects Responses to Stroma-directed Therapy in Mouse Models of Pancreatic Ductal Adenocarcinoma.

    Cao, Jianbo / Pickup, Stephen / Clendenin, Cynthia / Blouw, Barbara / Choi, Hoon / Kang, David / Rosen, Mark / O'Dwyer, Peter J / Zhou, Rong

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2018  Volume 25, Issue 7, Page(s) 2314–2322

    Abstract: Purpose: The dense stroma underlies the drug resistance of pancreatic ductal adenocarcinoma (PDA) and has motivated the development of stroma-directed drugs. Our objective is to test the concept that dynamic contrast-enhanced (DCE) MRI using FDA- ... ...

    Abstract Purpose: The dense stroma underlies the drug resistance of pancreatic ductal adenocarcinoma (PDA) and has motivated the development of stroma-directed drugs. Our objective is to test the concept that dynamic contrast-enhanced (DCE) MRI using FDA-approved contrast media, an imaging method sensitive to the tumor microenvironment, can detect early responses to stroma-directed drug.
    Experimental design: Imaging studies were performed in three mouse models exhibiting high desmoplastic reactions: the autochthonous PDA in genetically engineered mice (KPC), an orthotopic model in syngeneic mice, and a xenograft model of human PDA in athymic mice. An investigational drug, PEGPH20 (pegvorhyaluronidase alfa), which degrades hyaluronan (HA) in the stroma of PDA, was injected alone or in combination with gemcitabine.
    Results: At 24 hours after a single injection of PEGPH20,
    Conclusions: These data demonstrated a DCE-MRI marker,
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Pancreatic Ductal/diagnostic imaging ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Contrast Media ; Humans ; Hyaluronoglucosaminidase/pharmacokinetics ; Hyaluronoglucosaminidase/therapeutic use ; Image Enhancement ; Immunohistochemistry ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Imaging/standards ; Mice ; Pancreatic Neoplasms/diagnostic imaging ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Reproducibility of Results ; Stromal Cells/drug effects ; Treatment Outcome ; Tumor Microenvironment ; Pancreatic Neoplasms
    Chemical Substances Antineoplastic Agents ; Contrast Media ; Hyaluronoglucosaminidase (EC 3.2.1.35) ; PEGPH20 (EC 3.2.1.35)
    Language English
    Publishing date 2018-12-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-2276
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide.

    Schubert, David / Soucek, Thomas / Blouw, Barbara

    The European journal of neuroscience

    2009  Volume 29, Issue 7, Page(s) 1323–1334

    Abstract: Reduced glucose metabolism and astrocyte activation in selective areas of the brain are pathological features of Alzheimer's disease (AD). The underlying mechanisms of low energy metabolism and a molecular basis for preventing astrocyte activation are ... ...

    Abstract Reduced glucose metabolism and astrocyte activation in selective areas of the brain are pathological features of Alzheimer's disease (AD). The underlying mechanisms of low energy metabolism and a molecular basis for preventing astrocyte activation are not, however, known. Here we show that amyloid beta peptide (Abeta)-dependent astrocyte activation leads to a long-term decrease in hypoxia-inducible factor (HIF)-1alpha expression and a reduction in the rate of glycolysis. Glial activation and the glycolytic changes are reversed by the maintenance of HIF-1alpha levels with conditions that prevent the proteolysis of HIF-1alpha. Abeta increases the long-term production of reactive oxygen species (ROS) through the activation of nicotinamide adenine dinucleotide phosphate oxidase and reduces the amount of HIF-1alpha via the activation of the proteasome. ROS are not required for glial activation, but are required for the reduction in glycolysis. These data suggest a significant role for HIF-1alpha-mediated transcription in maintaining the metabolic integrity of the AD brain and identify the probable cause of the observed lower energy metabolism in afflicted areas. They may also explain the therapeutic success of metal chelators in animal models of AD.
    MeSH term(s) Alzheimer Disease ; Amyloid beta-Peptides/metabolism ; Animals ; Astrocytes/drug effects ; Astrocytes/physiology ; Cells, Cultured ; Deferoxamine/pharmacology ; Glucose/metabolism ; Glycolysis/physiology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Iron Chelating Agents/pharmacology ; Mice ; Mice, Inbred C57BL ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism
    Chemical Substances Amyloid beta-Peptides ; Hif1a protein, mouse ; Hif1a protein, rat ; Hypoxia-Inducible Factor 1, alpha Subunit ; Iron Chelating Agents ; Reactive Oxygen Species ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Glucose (IY9XDZ35W2) ; Deferoxamine (J06Y7MXW4D)
    Language English
    Publishing date 2009-03-23
    Publishing country France
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 645180-9
    ISSN 1460-9568 ; 0953-816X
    ISSN (online) 1460-9568
    ISSN 0953-816X
    DOI 10.1111/j.1460-9568.2009.06712.x
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  9. Article ; Online: The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44.

    Zhao, Chunmei / Thompson, Benjamin J / Chen, Kelly / Gao, Feng / Blouw, Barbara / Marella, Mathieu / Zimmerman, Susan / Kimbler, Trevor / Garrovillo, Sheryl / Bahn, Jesse / Huang, Lei / Huang, Zhongdong / Shepard, H Michael / Rosengren, Sanna / Thanos, Christopher D / Maneval, Daniel C

    Oncotarget

    2019  Volume 10, Issue 61, Page(s) 6561–6576

    Abstract: Hyaluronan accumulation in the tumor microenvironment is associated with poor prognosis in several solid human cancers. To understand the role of stromal hyaluronan in tumor progression, we engineered 3T3HAS3, a hyaluronan-producing fibroblast cell line, ...

    Abstract Hyaluronan accumulation in the tumor microenvironment is associated with poor prognosis in several solid human cancers. To understand the role of stromal hyaluronan in tumor progression, we engineered 3T3HAS3, a hyaluronan-producing fibroblast cell line, by lentiviral transduction of Balb/c 3T3 cells with the
    Language English
    Publishing date 2019-11-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.27302
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  10. Article: Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer.

    Blair, Alex B / Kim, Victoria M / Muth, Stephen T / Saung, May Tun / Lokker, Nathalie / Blouw, Barbara / Armstrong, Todd D / Jaffee, Elizabeth M / Tsujikawa, Takahiro / Coussens, Lisa M / He, Jin / Burkhart, Richard A / Wolfgang, Christopher L / Zheng, Lei

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2019  Volume 25, Issue 17, Page(s) 5351–5363

    Abstract: Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a ...

    Abstract Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component.
    Experimental design: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20.
    Results: Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8
    Conclusions: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/immunology ; Cancer-Associated Fibroblasts/drug effects ; Cancer-Associated Fibroblasts/immunology ; Cancer-Associated Fibroblasts/pathology ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/immunology ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Cell Movement ; Chemokines/immunology ; Chemokines/metabolism ; Female ; Humans ; Immunologic Memory/drug effects ; Immunologic Memory/immunology ; Immunosuppression ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloid Cells/drug effects ; Myeloid Cells/immunology ; Myeloid Cells/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/pathology ; Signal Transduction ; Stromal Cells/drug effects ; Stromal Cells/immunology ; Stromal Cells/pathology
    Chemical Substances Cancer Vaccines ; Chemokines
    Language English
    Publishing date 2019-06-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-4192
    Database MEDical Literature Analysis and Retrieval System OnLINE

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