Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel

Khalid A. Mohamedali, Ann T. Poblenz, Charles R. Sikes, Nora M. Navone, Philip E. Thorpe, Bryant G. Darnay, Michael G. Rosenblum

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF121/recombinant gelonin (rGel) strongly inhibited tumor growth. Fifty percent of treated animals had complete regression of bone tumors with no development of lytic bone lesions. Immunohistochemical analysis showed that VEGF121/rGel treatment suppressed tumor-mediated osteoclastogenesis in vivo. In vitro treatment of murine osteoclast precursors, both cell line (RAW264.7) and bone marrow-derived monocytes (BMM), revealed that VEGF121/rGel was selectively cytotoxic to osteoclast precursor cells rather than mature osteoclasts. VEGF 121/rGel cytotoxicity was mediated by Flt-1, which was down-regulated during osteoclast differentiation. Analysis by flow cytometry and reverse transcription-PCR showed that both BMM and RAW264.7 cells display high levels of Flt-1 but low levels of Flk-1. Internalization of VEGF121/rGel into osteoclast precursor cells was suppressed by pretreatment with an Flt-1 neutralizing antibody or by placenta growth factor but not with an Flk-1 neutralizing antibody. Thus, VEGF121/rGel inhibits osteoclast maturation in vivo and it seems that this process is important in the resulting suppression of skeletal osteolytic lesions. This is a novel and unique mechanism of action for this class of agents and suggests a potentially new approach for treatment or prevention of tumor growth in bone.

Original languageEnglish (US)
Pages (from-to)10919-10928
Number of pages10
JournalCancer research
Volume66
Issue number22
DOIs
StatePublished - Nov 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mohamedali, K. A., Poblenz, A. T., Sikes, C. R., Navone, N. M., Thorpe, P. E., Darnay, B. G., & Rosenblum, M. G. (2006). Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel. Cancer research, 66(22), 10919-10928. https://doi.org/10.1158/0008-5472.CAN-06-0459