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Breast Cancer Cell-Derived Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor Are Chemoattractants for Bone Marrow Stromal Stem Cells

Ritter, Edmond MD*; Perry, Adam MD*; Yu, Jack MD, DDS*; Wang, Thomas MD, PhD*; Tang, Lawton MD; Bieberich, Erhard PhD†

doi: 10.1097/SLA.0b013e31816401d5
Original Articles

Objective: Recent efforts by the scientific community to characterize the complex interplay between different cell types involved in the development of tumors have led us to investigate the roles of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) in the development of breast cancer.

Methods: Using modified Boyden chamber assays, we measured the in vitro migration effect on murine mesenchymal stem cells (MSCs). Additionally, we assayed for the presence of receptors for these growth factors on MSCs, and for the presence of VEGF and FGF2 in breast cancer-conditioned media. We measured the change in migration of MSCs toward breast cancer when we depleted these growth factors from breast cancer-conditioned media. Further, we conducted a series of standard curve migration assays for basal media supplemented with physiologic concentrations of VEGF and FGF2.

Results: Analysis of gene expression and protein analysis demonstrated the expression of FGF2 and VEGF by the breast cancer cells, and the presence of VEGF (FLK1) and FGF2 receptors on the MSCs. We also demonstrated a reduction in migration when we antibody-depleted VEGF and FGF2 from breast cancer-conditioned media. Additionally, we found the physiologic concentrations of VEGF and FGF2 at 12 and 15 ng/mL, respectively.

Conclusions: We demonstrate that VEGF and FGF2 induce migration of MSCs are secreted by breast cancer cells, their receptors are present on MSCs, and depletion of these growth factors reduces migration, and are therefore 2 relevant growth factors for MSC migration toward breast cancer cells.

As breast cancers grow, mesenchymal stem cells (MSCs) are attracted to, and converted into, tumor stroma. Fibroblast growth factor 2 and vascular endothelial growth factor are secreted by breast cancer cells, bind to receptors on adult MSCs, and cause migration of MSCs toward breast cancer in an in vitro model.

From the *Department of Surgery, and †Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, Georgia.

The first two authors contributed equally to this study.

Supported in part by NIH Grant R01 NS46835, the Susan Komen Breast Cancer Research Foundation (BCTR0600658), and funding obtained from the Department of Surgery, Medical College of Georgia.

Reprints: Edmond F. Ritter, MD, Department of Plastic and Reconstructive Surgery, Medical College of Georgia, 1467 Harper Street, HB 5040, Augusta, GA 30912. E-mail: eritter@mcg.edu.

© 2008 Lippincott Williams & Wilkins, Inc.