Antitumor effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation

Roderich E. Schwarz, Niranjan Awasthi, Srivani Konduri, Lauren Caldwell, Danielle Cafasso, Margaret A. Schwarz

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy. The presence of both cellular and stromal fibronectin (FN) and its interaction with integrins is necessary for PDAC progression. We tested the efficacy of endothelial monocyte-activating polypeptide II (EMAP II) to inhibit PDAC progression and its ability to interfere with FN-integrin angiogenesis signaling. In heterotopic PDAC tumors EMAP II caused a significant reduction (>65%) in tumor growth, accompanied by a >50% and 44% decrease in microvessel density and proliferative activity, respectively. EMAP II therapy caused a 62% and 56% reduction in host and tumor cell FN expression. Cultured PDAC cells expressed αVβ3 and α5β1 integrins. In vitro EMAP II had limited antiproliferative effects on ASPC-1, but a pronounced antiproliferative effect on endothellial cells. 3D FN matrices increased ASPC-1 cell proliferation by >50%, and this induction was significantly blocked by α3, α5, α6 and αV integrin funtional blocking antibodies, while α1, α2 and α4 antibodies had no effect. EMAP II also inhibited 3D FN-matrix induced ASPC-1 proliferation by >43% at 20 μM. These findings suggest that EMAP II demonstrates significant antitumor activity against PDAC cells, and that this effect may be in part mediated through targeted interference with stromal FN-integrin dependent PDAC cell proliferation.

Original languageEnglish (US)
Pages (from-to)632-639
Number of pages8
JournalCancer Biology and Therapy
Volume9
Issue number8
DOIs
StatePublished - Apr 15 2010

Keywords

  • Cell proliferation
  • EMAP II
  • Fibronectin
  • Integrin
  • Pancreatic cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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