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Chemotherapy Induces Macrophage Chemoattractant Protein-1 Production in Ovarian Cancer
  1. Lisa M. Rogers, MS,
  2. Melissa A. Geller, MD*,
  3. Tri M. Bui-Nguyen, PhD and
  4. Sundaram Ramakrishnan, PhD*,
  1. * Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, and
  2. Department of Pharmacology, University of Minnesota, Minneapolis, MN.
  1. Address correspondence and reprint requests to Melissa Geller, MD, Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, MMC 395, 420 Delaware St, SE Minneapolis, MN 55455. E-mail: gelle005{at}umn.edu.

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.

  • Macrophage
  • MCP-1
  • Ovarian cancer

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Footnotes

  • The authors declare that there are no conflicts of interest.

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