Cancer Research Aziza Shad Sign up for Cancer Research eTOC's
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krishnan, J.
Right arrow Articles by Sleeman, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krishnan, J.
Right arrow Articles by Sleeman, J. P.
[Cancer Research 63, 713-722, February 1, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Differential in Vivo and in Vitro Expression of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in Tumors and Its Relationship to Lymphatic Metastasis in Immunocompetent Rats1

Jaya Krishnan, Vladimir Kirkin, Anja Steffen, Martin Hegen, Debbie Weih, Stanislav Tomarev, Jörg Wilting and Jonathan P. Sleeman2

Forschungszentrum Karlsruhe, Institute of Genetics, D-76021 Karlsruhe, Germany [J. K., V. K., A. S., M. H., D. W., J. P. S.]; Laboratory of Molecular and Developmental Biology, National Eye Institute, NIH, Bethesda, Maryland 20892 [S. T.]; and Kinderklinik und Poliklinik Göttingen, 37075 Göttingen, Germany [J. W.]

The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival. A number of clinical and experimental studies suggest that tumor-induced lymphangiogenesis driven by vascular endothelial growth factor (VEGF)-C- and/or VEGF-D-induced activation of VEGF receptor (VEGFR)-3 may promote metastasis to regional lymph nodes. Here we show that constitutive VEGF-C and VEGF-D expression by tumor cells of diverse origin grown in tissue culture does not correlate with metastatic potential in vivo. However, tumors derived from cell lines that do not constitutively express VEGF-C or VEGF-D in tissue culture can nevertheless express one or both of these factors. We demonstrate that both tumor and stromal cells can contribute to this expression, suggesting that tumor cell-host interactions determine tumor expression of VEGF-C and VEGF-D. Using immunocompetent rat mammary tumor models, we show in two ways that this expression can promote metastasis via the lymphatics. Firstly, ectopic expression of a soluble VEGFR-3 receptor globulin protein in MT-450 tumor cells that are highly metastatic via the lymphatics blocked VEGF-C and VEGF-D activity and suppressed metastasis formation in both the regional lymph nodes and the lungs. Secondly, ectopic expression in the weakly metastatic NM-081 cell line of a mutant form of VEGF-C that is only able to activate VEGFR-3 strongly promoted metastasis of these cells to the regional lymph nodes and lung. These data show that expression of VEGF-C and VEGF-D in tissue culture does not reflect expression in vivo and that activation of VEGFR-3 in the absence of VEGFR-2 activation is sufficient to promote tumor-induced lymphangiogenesis and metastasis, and they support the notion that blockade of VEGFR-3 activation will be useful as a novel form of cancer therapy.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
T. Holopainen, H. Huang, C. Chen, K. E. Kim, L. Zhang, F. Zhou, W. Han, C. Li, J. Yu, J. Wu, et al.
Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment
Cancer Res., June 1, 2009; 69(11): 4656 - 4664.
[Abstract] [Full Text] [PDF]

Home page
 Jpn J Clin OncolHome page
T. Miyazaki, N. Okada, K. Ishibashi, K. Ogata, T. Ohsawa, T. Ishiguro, H. Nakada, M. Yokoyama, M. Matsuki, H. Kato, et al.
Clinical Significance of Plasma Level of Vascular Endothelial Growth Factor-C in Patients with Colorectal Cancer
Jpn. J. Clin. Oncol., December 1, 2008; 38(12): 839 - 843.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. S. Sundar and T. S. Ganesan
Role of Lymphangiogenesis in Cancer
J. Clin. Oncol., September 20, 2007; 25(27): 4298 - 4307.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Hirakawa, L. F. Brown, S. Kodama, K. Paavonen, K. Alitalo, and M. Detmar
VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites
Blood, February 1, 2007; 109(3): 1010 - 1017.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. Laakkonen, M. Waltari, T. Holopainen, T. Takahashi, B. Pytowski, P. Steiner, D. Hicklin, K. Persaud, J. R. Tonra, L. Witte, et al.
Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth
Cancer Res., January 15, 2007; 67(2): 593 - 599.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. Wissmann and M. Detmar
Pathways Targeting Tumor Lymphangiogenesis
Clin. Cancer Res., December 1, 2006; 12(23): 6865 - 6868.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
A. Schmeisser, M. Christoph, A. Augstein, R. Marquetant, M. Kasper, R.C. Braun-Dullaeus, and R.H. Strasser
Apoptosis of human macrophages by Flt-4 signaling: Implications for atherosclerotic plaque pathology
Cardiovasc Res, September 1, 2006; 71(4): 774 - 784.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Roberts, B. Kloos, M. Cassella, S. Podgrabinska, K. Persaud, Y. Wu, B. Pytowski, and M. Skobe
Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2.
Cancer Res., March 1, 2006; 66(5): 2650 - 2657.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Miyata, S. Kanda, K. Ohba, K. Nomata, Y. Hayashida, J. Eguchi, T. Hayashi, and H. Kanetake
Lymphangiogenesis and Angiogenesis in Bladder Cancer: Prognostic Implications and Regulation by Vascular Endothelial Growth Factors-A, -C, and -D
Clin. Cancer Res., February 1, 2006; 12(3): 800 - 806.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Y. Wong, H. Haack, D. Crowley, M. Barry, R. T. Bronson, and R. O. Hynes
Tumor-Secreted Vascular Endothelial Growth Factor-C Is Necessary for Prostate Cancer Lymphangiogenesis, but Lymphangiogenesis Is Unnecessary for Lymph Node Metastasis
Cancer Res., November 1, 2005; 65(21): 9789 - 9798.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo
Vascular Endothelial Cell Growth Factor Receptor 3-Mediated Activation of Lymphatic Endothelium Is Crucial for Tumor Cell Entry and Spread via Lymphatic Vessels
Cancer Res., June 1, 2005; 65(11): 4739 - 4746.
[Abstract] [Full Text] [PDF]

Home page
 aacredbookHome page
T. Tammela, C. Heckman, and K. Alitalo
Lymphangiogenesis and Metastasis
Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 67 - 73.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Alitalo, S. Mohla, and E. Ruoslahti
Lymphangiogenesis and Cancer: Meeting Report
Cancer Res., December 15, 2004; 64(24): 9225 - 9229.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H. Kurahara, S. Takao, K. Maemura, H. Shinchi, S. Natsugoe, and T. Aikou
Impact of Vascular Endothelial Growth Factor-C and -D Expression in Human Pancreatic Cancer: Its Relationship to Lymph Node Metastasis
Clin. Cancer Res., December 15, 2004; 10(24): 8413 - 8420.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
I. Crnic, K. Strittmatter, U. Cavallaro, L. Kopfstein, L. Jussila, K. Alitalo, and G. Christofori
Loss of Neural Cell Adhesion Molecule Induces Tumor Metastasis by Up-regulating Lymphangiogenesis
Cancer Res., December 1, 2004; 64(23): 8630 - 8638.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
M J Currie, V Hanrahan, S P Gunningham, H R Morrin, C Frampton, C Han, B A Robinson, and S B Fox
Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1{alpha}) and the HIF-1{alpha} target gene DEC1, but not lymph node metastasis in primary human breast carcinomas
J. Clin. Pathol., August 1, 2004; 57(8): 829 - 834.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain
Peritumor Lymphatics Induced by Vascular Endothelial Growth Factor-C Exhibit Abnormal Function
Cancer Res., July 1, 2004; 64(13): 4400 - 4404.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. He, I. Rajantie, M. Ilmonen, T. Makinen, M. J. Karkkainen, P. Haiko, P. Salven, and K. Alitalo
Preexisting Lymphatic Endothelium but not Endothelial Progenitor Cells Are Essential for Tumor Lymphangiogenesis and Lymphatic Metastasis
Cancer Res., June 1, 2004; 64(11): 3737 - 3740.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
P. Hamrah, L. Chen, Q. Zhang, and M. R. Dana
Novel Expression of Vascular Endothelial Growth Factor Receptor (VEGFR)-3 and VEGF-C on Corneal Dendritic Cells
Am. J. Pathol., July 1, 2003; 163(1): 57 - 68.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.