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

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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

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Bone Remodeling
Osteoclasts
Blood Vessels
Prostate
Growth
Neoplasms
Bone Development
Neutralizing Antibodies
Osteogenesis
Vascular Endothelial Growth Factor A
Monocytes
Bone Marrow
Gelonium multiflorum GEL protein
Nude Mice
Reverse Transcription
Flow Cytometry
Neoplasm Metastasis
Bone and Bones
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel. / Mohamedali, Khalid A.; Poblenz, Ann T.; Sikes, Charles R.; Navone, Nora M.; Thorpe, Philip E.; Darnay, Bryant G.; Rosenblum, Michael G.

In: Cancer Research, Vol. 66, No. 22, 15.11.2006, p. 10919-10928.

Research output: Contribution to journalArticle

Mohamedali, KA, Poblenz, AT, Sikes, CR, Navone, NM, Thorpe, PE, Darnay, BG & Rosenblum, MG 2006, 'Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel', Cancer Research, vol. 66, no. 22, pp. 10919-10928. https://doi.org/10.1158/0008-5472.CAN-06-0459
Mohamedali KA, Poblenz AT, Sikes CR, Navone NM, Thorpe PE, Darnay BG et al. Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel. Cancer Research. 2006 Nov 15;66(22):10919-10928. https://doi.org/10.1158/0008-5472.CAN-06-0459
Mohamedali, Khalid A. ; Poblenz, Ann T. ; Sikes, Charles R. ; Navone, Nora M. ; Thorpe, Philip E. ; Darnay, Bryant G. ; Rosenblum, Michael G. / Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel. In: Cancer Research. 2006 ; Vol. 66, No. 22. pp. 10919-10928.
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