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Roche, Francis P.
Alternative names
Publications (6 of 6) Show all publications
Roche, F. P., Pietilä, I., Kaito, H., Sjöström, E. O., Sobotzki, N., Noguer, O., . . . Claesson-Welsh, L. (2018). Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity. Molecular Cancer Therapeutics, 17(9), 1961-1972
Open this publication in new window or tab >>Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
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2018 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 17, no 9, p. 1961-1972Article in journal (Refereed) Published
Abstract [en]

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-356836 (URN)10.1158/1535-7163.MCT-18-0097 (DOI)000444041300015 ()29945872 (PubMedID)
Funder
Swedish Cancer Society, 16 0585Swedish Cancer Society, 16 0520Swedish Research Council, 2015-02375_3Swedish Research Council, 2016-01085
Note

I. Pietilä and H. Kaito contributed equally to this article.

Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-11-26Bibliographically approved
Mitran, B., Güler, R., Roche, F. P., Lindström, E., Selvaraju, R., Fleetwood, F., . . . Löfblom, J. (2018). Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model. Theranostics, 8(16), 4462-4476
Open this publication in new window or tab >>Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model
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2018 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 8, no 16, p. 4462-4476Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (Z(VEGFR2)-Bp(2)) for in vivo visualization of VEGFR2 expression in GBM.

Methods: Z(VEGFR2)-Bp(2) coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed.

Results: [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) bound specifically to VEGFR2 (K-D=33 +/- 18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 mu g [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were significantly higher than the ratios observed for the 40 mu g injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images.

Conclusion: The anti-VEGFR2 affibody conjugate [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were higher compared to other VEGFR2 imaging probes. [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL, 2018
Keywords
VEGFR2, affibody molecule, molecular imaging, SPECT, orthotopic glioma model, in vivo
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-365854 (URN)10.7150/thno.24395 (DOI)000444104300013 ()30214632 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 621-2012-5236Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353VINNOVA, 2016-04060VINNOVA, 2017-02015Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society, CAN2017/649Swedish Cancer Society, CAN2013/586Swedish Cancer Society, CAN2016/463Swedish Cancer Society, CAN2014/474Swedish Cancer Society, CAN2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN2016/585
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet

Available from: 2018-11-15 Created: 2018-11-15 Last updated: 2018-11-15Bibliographically approved
Mitran, B., Guler, R., Roche, F. P., Lindström, E., Selvaraju, R., Heetwood, F., . . . Löfblom, J. (2017). Novel high affinity affibody for radionuclide imaging of VEGFR2 in glioma vasculature: proof-of-principle in murine model. European Journal of Nuclear Medicine and Molecular Imaging, 44, S239-S239
Open this publication in new window or tab >>Novel high affinity affibody for radionuclide imaging of VEGFR2 in glioma vasculature: proof-of-principle in murine model
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2017 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S239-S239Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2017
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-377080 (URN)000455019400225 ()
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-02-21Bibliographically approved
Li, X., Padhan, N., Sjöström, E. O., Roche, F. P., Testini, C., Honkura, N., . . . Claesson-Welsh, L. (2016). VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications, 7, Article ID 11017.
Open this publication in new window or tab >>VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed) Published
Abstract [en]

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-288617 (URN)10.1038/ncomms11017 (DOI)000372721400001 ()27005951 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 294556 BBBARRIERWenner-Gren Foundations
Available from: 2016-05-11 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
Roche, F., Sipilä, K., Honjo, S., Staffan, J., Tugues, S., Heino, J. & Claesson-Welsh, L. (2015). Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha 2 integrin. Matrix Biology, 48, 89-99
Open this publication in new window or tab >>Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha 2 integrin
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2015 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 48, p. 89-99Article in journal (Refereed) Published
Abstract [en]

The plasma protein histidine-rich glycoprotein (HRG) affects the morphology and function of both endothelial cells (ECs) and monocytes/macrophages in cancer. Here, we examined the mechanism of action of HRG's effect on ECs. HRG suppressed adhesion, spreading and migration of ECs specifically on collagen I (COL I) whereas ECs seeded on other extracellular matrix proteins were insensitive to HRG. HRG did not bind specifically to COL I or to the α-integrin binding site on collagen, GFOGER. Furthermore, HRG's inhibition of EC adhesion was not dependent upon heparan sulfate (HS) moieties as heparitinase-treated ECs remained sensitive to HRG. C2C12 cells expressing α2 integrin, the major collagen-binding α-integrin subunit in ECs, showed increased binding of HRG compared with wild type C2C12 cells lacking the α2 subunit. Recombinant α2 I-domain protein bound HRG and to a higher extent when in active conformation. However, the α2 I-domain bound weakly to HRG compared with COL I and the purified α2β1 ectodomain complex failed to retain HRG. We conclude that HRG binds to α2 integrin through low-affinity interactions in a HS-independent manner, thereby blocking EC-adhesion to COL I.

Keywords
HRG; Adhesion; Integrin; Endothelial cells; Collagen
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-273699 (URN)10.1016/j.matbio.2015.06.002 (DOI)000366617000009 ()26051322 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2016-01-17 Created: 2016-01-17 Last updated: 2018-01-10Bibliographically approved
Roche, F. P., Ohlin, E., Essand, M. & Claesson-Welsh, L. (2013). Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer. Paper presented at 16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 15-18, 2013, Salt Lake City, UT. Molecular Therapy, 21, S241-S241
Open this publication in new window or tab >>Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer
2013 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S241-S241Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203417 (URN)000319858400629 ()
Conference
16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 15-18, 2013, Salt Lake City, UT
Available from: 2013-07-10 Created: 2013-07-10 Last updated: 2017-12-06Bibliographically approved
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