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

Jong Hyuk Kim, Aric M. Frantz, Katie L. Anderson, Ashley J. Graef, Milcah C. Scott, Sally Robinson, Leslie C. Sharkey, Timothy D. O'Brien, Erin B. Dickerson, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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, 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.

Original languageEnglish (US)
Pages (from-to)155-164
Number of pages10
JournalExperimental Cell Research
Volume323
Issue number1
DOIs
StatePublished - Apr 15 2014

Bibliographical note

Funding Information:
The authors thank Drs. Chris Pennel and Nicola Mason for review of the manuscript and insightful suggestions. This work was supported by grants CHF 422 , CHF 1131 , and CHF 1429 from the AKC Canine Health Foundation , DM06CO-002 from the National Canine Cancer Foundation , D10CA-501 from Morris Animal Foundation , and by funds from the Animal Cancer Care and Research Program, University of Minnesota . JHK was supported by a Fellowship from Morris Animal Foundation ( D13CA-400 ). KLA was supported by grant T35 RR032321 from the NIH . AMF was supported by the DVM/PhD combined degree program of the College of Veterinary Medicine, University of Minnesota , by a pre-doctoral fellowship from Morris Animal Foundation ( D09CA-405 ) and by a doctoral dissertation fellowship from the Graduate School, University of Minnesota . SR was supported by NIH T32 Comparative Medicine and Pathology training grant T32 RR018719 .

Keywords

  • Canine
  • Gene expression profiling
  • Hemangiosarcoma
  • Interleukin-8
  • Tumor microenvironment

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