Chemotherapy induces macrophage chemoattractant protein-1 production in ovarian cancer

Melissa A. Getter, Tri M. Bui-Nguyen, Lisa M. Rogers, Sundaram Ramakrishnan

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Objectives: Tumor infiltrating macrophages play an important role in tumor progression. Macrophage chemoattractant protein-1 (MCP-1) is one of the major chemokines responsible for inducing macrophage migration. Our objective was to investigate chemotherapy-induced modulation of MCP-1 in ovarian cancer by investigating macrophage infiltration, tumor vascularity, and MCP-1 expression after chemotherapy exposure. Methods: MA-148 ovarian cancer cells were treated with paclitaxel (43 pg/mL) and carboplatin (5μg/mL) alone or in combination. Reverse transcription-polymerase chain reaction determined MCP-1 transcript levels and enzyme-linked immunosorbent assay evaluated MCP-1 protein production at multiple time points. The effect of kinase inhibitors on MCP-1 expression was investigated. In vivo MCP-1 production was examined in tumor-bearing mice and immunohistochemistry with fluorescein isothiocyanate conjugated anti-mouse F4/80 antibody, phycoerythrin-anti-CD31, and terminal deoxynucleotide transferase dUTP nick-end labeling assay were performed. Results: Macrophage chemoattractant protein-1 transcript levels were up-regulated in MA-148 after treatment with paclitaxel and carboplatin individually and in combination. The greatest elevation was seen with combination therapy: 2.5-fold increase in the MCP-1 protein levels from baseline (P = 0.011) with the mitogen-activated protein kinase and janus kinases/signal transducers and activators of transcription pathways appearing to be involved in the regulation of MCP-1 production. In vivo mouse studies confirmed increased MCP-1 production after chemotherapy; however, there was no significant difference in macrophage, apoptosis, or vessel density. Conclusions: Macrophage chemoattractant protein-1 is up-regulated in ovarian cancer after chemotherapy in vitro and in vivo. Whether MCP-1 production is increased because of a stress-induced response or a scavenger response promoting macrophage infiltration remains unknown. Chemotherapy induction of MCP-1 in ovarian cancer suggests this chemokine plays an important role in the immune response occurring after chemotherapy exposure.

Original languageEnglish (US)
Pages (from-to)918-925
Number of pages8
JournalInternational Journal of Gynecological Cancer
Volume20
Issue number6
DOIs
StatePublished - Aug 2010

Keywords

  • MCP-1
  • Macrophage
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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