Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.

Abstract

Angiogenesis is essential for solid tumor progression. Here, the authors interrogate the proteome of pancreatic cancer endothelium via phage display and identify hornerin as a critical protein whose expression is essential to maintain the pancreatic cancer vasculature through a VEGF-independent mechanism.

Related collections

Most cited references 51

Record: found
Abstract: found
Article: not found

Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

D Senger, S Galli, A. Dvorak … (1983)

Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.

0 comments Cited 336 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

Stephen Johnston, John Pippen, Xavier Pivot … (2009)

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

0 comments Cited 239 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature).

Ingo Marenholz, Claus W. Heizmann, Günter Fritz (2004)

The S100 protein family is the largest subgroup within the superfamily of proteins carrying the Ca2+-binding EF-hand motif. Despite their small molecular size and their conserved functional domain of two distinct EF-hands, S100 proteins developed a plethora of tissue-specific intra- and extracellular functions. Accordingly, various diseases such as cardiomyopathies, neurodegenerative and inflammatory disorders, and cancer are associated with altered S100 protein levels. Here, we review the different S100 protein functions and related diseases from an evolutionary point of view. We analyzed the structural variations, which are the basis of functional diversification, as well as the genomic organization of the S100 family in human and compared it with the S100 repertoires in mouse and rat. S100 genes and proteins are highly conserved between the different mammalian species. Moreover, we identified evolutionary related subgroups of S100 proteins within the three species, which share functional similarity and form subclusters on the genomic level. The available S100-specific mouse models are summarized and the consequences of our results are discussed with regard to the use of genetically engineered mice as human disease models. An update of the S100 nomenclature is included, because some of the recently identified S100 genes and pseudogenes had to be renamed. Copyright 2004 Elsevier Inc.

0 comments Cited 195 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Kimberly A. Kelly: kak3x@virginia.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 15 September 2017

Publication date PMC-release: 15 September 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 552

Affiliations

[1 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Cardiovascular Research Center, , The University of Virginia, ; Box 801394, Charlottesville, Virginia 22908 USA

[2 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Department of Biomedical Engineering, , The University of Virginia, ; Box 800759 Health System, Charlottesville, Virginia 22908 USA

[3 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Department of Pathology, , The University of Virginia, ; Box 800904, Charlottesville, Virginia 22908 USA

[4 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Department of Biochemistry and Molecular Genetics, , The University of Virginia, ; Box 800733, Charlottesville, 22908 Virginia USA

Author information

Bo Ning http://orcid.org/0000-0002-6006-5696

Article

Publisher ID: 488

DOI: 10.1038/s41467-017-00488-6

PMC ID: 5601918

PubMed ID: 28916756

SO-VID: a96f1745-a219-4c0a-85a1-51924748f882

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 26 June 2015

Date accepted : 4 July 2017

Custom metadata

ScienceOpen disciplines: Uncategorized

Data availability:

ScienceOpen disciplines: Uncategorized

Comments

Comment on this article

scite_

Cited by 8

See all cited by

Most referenced authors 1,056

See all reference authors

- Version 1

Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity

Read this article at

Abstract

Abstract

Related collections

Resource Identification

Most cited references 51

Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature).

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 176

Cited by 8

Most referenced authors 1,056