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Title: Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment

Abstract

Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, wemore » hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. - Highlights: • IL-8 is expressed in canine hemangiosarcoma tumor samples and cell lines. • IL-8 transduces a relevant biological signal in canine hemangiosarcoma cells. • IL-8 gene signature is associated with reactive tumor microenvironments. • IL-8 potentiates tumor cell survival and engraftment into host tissues. • Canine hemangiosarcoma provides a unique comparative model for IL-8 studies.« less

Authors:
 [1]; ; ; ;  [1];  [2];  [1];  [1];  [1]
  1. Department of Veterinary Clinical Science, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States)
  2. Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN (United States)
Publication Date:
OSTI Identifier:
22395887
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 323; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALBUMINS; ANIMAL TISSUES; ANTIBODIES; BLOOD SERUM; CALCIUM; DOGS; IN VITRO; IN VIVO; MESSENGER-RNA; MICE; NEOPLASMS; RECEPTORS; TUMOR CELLS

Citation Formats

Kim, Jong-Hyuk, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Frantz, Aric M., Anderson, Katie L., Graef, Ashley J., Scott, Milcah C., Robinson, Sally, Sharkey, Leslie C., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, O'Brien, Timothy D., Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, Dickerson, Erin B., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Modiano, Jaime F., E-mail: modiano@umn.edu, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. United States: N. p., 2014. Web. doi:10.1016/J.YEXCR.2014.02.020.
Kim, Jong-Hyuk, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Frantz, Aric M., Anderson, Katie L., Graef, Ashley J., Scott, Milcah C., Robinson, Sally, Sharkey, Leslie C., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, O'Brien, Timothy D., Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, Dickerson, Erin B., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Modiano, Jaime F., E-mail: modiano@umn.edu, & Masonic Cancer Center, University of Minnesota, Minneapolis, MN. Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. United States. https://doi.org/10.1016/J.YEXCR.2014.02.020
Kim, Jong-Hyuk, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Frantz, Aric M., Anderson, Katie L., Graef, Ashley J., Scott, Milcah C., Robinson, Sally, Sharkey, Leslie C., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, O'Brien, Timothy D., Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, Dickerson, Erin B., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, Modiano, Jaime F., E-mail: modiano@umn.edu, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN. 2014. "Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment". United States. https://doi.org/10.1016/J.YEXCR.2014.02.020.
@article{osti_22395887,
title = {Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment},
author = {Kim, Jong-Hyuk and Masonic Cancer Center, University of Minnesota, Minneapolis, MN and Frantz, Aric M. and Anderson, Katie L. and Graef, Ashley J. and Scott, Milcah C. and Robinson, Sally and Sharkey, Leslie C. and Masonic Cancer Center, University of Minnesota, Minneapolis, MN and O'Brien, Timothy D. and Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN and Dickerson, Erin B. and Masonic Cancer Center, University of Minnesota, Minneapolis, MN and Modiano, Jaime F., E-mail: modiano@umn.edu and Masonic Cancer Center, University of Minnesota, Minneapolis, MN},
abstractNote = {Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into “IL-8 high” and “IL-8 low” groups. Genome-wide gene expression profiling showed that samples in the “IL-8 high” tumor group were enriched for genes associated with a “reactive microenvironment,” including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA. - Highlights: • IL-8 is expressed in canine hemangiosarcoma tumor samples and cell lines. • IL-8 transduces a relevant biological signal in canine hemangiosarcoma cells. • IL-8 gene signature is associated with reactive tumor microenvironments. • IL-8 potentiates tumor cell survival and engraftment into host tissues. • Canine hemangiosarcoma provides a unique comparative model for IL-8 studies.},
doi = {10.1016/J.YEXCR.2014.02.020},
url = {https://www.osti.gov/biblio/22395887}, journal = {Experimental Cell Research},
issn = {0014-4827},
number = 1,
volume = 323,
place = {United States},
year = {Tue Apr 15 00:00:00 EDT 2014},
month = {Tue Apr 15 00:00:00 EDT 2014}
}