Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model

Brandt Whitehurst, Michael J. Flister, Juhi Bagaitkar, Lisa Volk, Christopher M. Bivens, Brent Pickett, Emely Castro-Rivera, Rolf A. Brekken, Robert D. Gerard, Sophia Ran

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.

Original languageEnglish (US)
Pages (from-to)2181-2191
Number of pages11
JournalInternational Journal of Cancer
Volume121
Issue number10
DOIs
StatePublished - Nov 15 2007

Fingerprint

Vascular Endothelial Growth Factor Receptor-3
Lymphatic Vessels
Vascular Endothelial Growth Factor A
Breast Neoplasms
Angiopoietin-2
Lymphangiogenesis
Neoplasm Metastasis
Therapeutics
Endothelial Cells
Neoplasms
Antibodies
Vascular Tissue Neoplasms
Vascular Endothelial Growth Factor C
Lymphatic Metastasis
Angiogenesis Inducing Agents
Neutralizing Antibodies
Luciferases
Blood Vessels
Macrophages

Keywords

  • Breast cancer
  • Lymphangiogenesis
  • Metastasis
  • VEGF-A
  • VEGFR-3

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Whitehurst, B., Flister, M. J., Bagaitkar, J., Volk, L., Bivens, C. M., Pickett, B., ... Ran, S. (2007). Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. International Journal of Cancer, 121(10), 2181-2191. https://doi.org/10.1002/ijc.22937

Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. / Whitehurst, Brandt; Flister, Michael J.; Bagaitkar, Juhi; Volk, Lisa; Bivens, Christopher M.; Pickett, Brent; Castro-Rivera, Emely; Brekken, Rolf A.; Gerard, Robert D.; Ran, Sophia.

In: International Journal of Cancer, Vol. 121, No. 10, 15.11.2007, p. 2181-2191.

Research output: Contribution to journalArticle

Whitehurst, B, Flister, MJ, Bagaitkar, J, Volk, L, Bivens, CM, Pickett, B, Castro-Rivera, E, Brekken, RA, Gerard, RD & Ran, S 2007, 'Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model', International Journal of Cancer, vol. 121, no. 10, pp. 2181-2191. https://doi.org/10.1002/ijc.22937
Whitehurst, Brandt ; Flister, Michael J. ; Bagaitkar, Juhi ; Volk, Lisa ; Bivens, Christopher M. ; Pickett, Brent ; Castro-Rivera, Emely ; Brekken, Rolf A. ; Gerard, Robert D. ; Ran, Sophia. / Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. In: International Journal of Cancer. 2007 ; Vol. 121, No. 10. pp. 2181-2191.
@article{75df3f978cc8462eae73742556dd4a8b,
title = "Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model",
abstract = "Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70{\%} and 80{\%}, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32{\%}, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50{\%} by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.",
keywords = "Breast cancer, Lymphangiogenesis, Metastasis, VEGF-A, VEGFR-3",
author = "Brandt Whitehurst and Flister, {Michael J.} and Juhi Bagaitkar and Lisa Volk and Bivens, {Christopher M.} and Brent Pickett and Emely Castro-Rivera and Brekken, {Rolf A.} and Gerard, {Robert D.} and Sophia Ran",
year = "2007",
month = "11",
day = "15",
doi = "10.1002/ijc.22937",
language = "English (US)",
volume = "121",
pages = "2181--2191",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model

AU - Whitehurst, Brandt

AU - Flister, Michael J.

AU - Bagaitkar, Juhi

AU - Volk, Lisa

AU - Bivens, Christopher M.

AU - Pickett, Brent

AU - Castro-Rivera, Emely

AU - Brekken, Rolf A.

AU - Gerard, Robert D.

AU - Ran, Sophia

PY - 2007/11/15

Y1 - 2007/11/15

N2 - Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.

AB - Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.

KW - Breast cancer

KW - Lymphangiogenesis

KW - Metastasis

KW - VEGF-A

KW - VEGFR-3

UR - http://www.scopus.com/inward/record.url?scp=35348817465&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35348817465&partnerID=8YFLogxK

U2 - 10.1002/ijc.22937

DO - 10.1002/ijc.22937

M3 - Article

C2 - 17597103

AN - SCOPUS:35348817465

VL - 121

SP - 2181

EP - 2191

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 10

ER -