VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis

The EMBO Journal
Jianying DongN Ferrara

Abstract

We generated VEGF-null fibrosarcomas from VEGF-loxP mouse embryonic fibroblasts to investigate the mechanisms of tumor escape after VEGF inactivation. These cells were found to be tumorigenic and angiogenic in vivo in spite of the absence of tumor-derived VEGF. However, VEGF derived from host stroma was readily detected in the tumor mass and treatment with a newly developed anti-VEGF monoclonal antibody substantially inhibited tumor growth. The functional significance of stroma-derived VEGF indicates that the recruitment of stromal cells is critical for the angiogenic and tumorigenic properties of these cells. Here we identified PDGF AA as the major stromal fibroblast chemotactic factor produced by tumor cells, and demonstrated that disrupting the paracrine PDGFR alpha signaling between tumor cells and stromal fibroblasts by soluble PDGFR alpha-IgG significantly reduced tumor growth. Thus, PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth. Our findings highlight a novel aspect of PDGFR alpha signaling in tumorigenesis.

References

Feb 1, 1990·Journal of Neuro-oncology·G R HarshL T Williams
Jan 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·K ForsbergB Westermark
Mar 14, 1998·Proceedings of the National Academy of Sciences of the United States of America·M Skobe, N E Fusenig
Sep 24, 1999·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·N Ferrara
May 12, 2000·Nature Cell Biology·X LiU Eriksson
Jun 30, 2000·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·I SulzbacherA Chott
Jul 6, 2000·The American Journal of Pathology·J KishimotoR E Burgeson
Sep 23, 2000·Nature·P Carmeliet, R K Jain
Apr 12, 2001·The Journal of Biological Chemistry·D G GilbertsonC E Hart
May 1, 2001·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·H PilchP Vaupel
Jun 13, 2001·Methods in Enzymology·J Rak, R S Kerbel
Feb 8, 2002·Archives of Biochemistry and Biophysics·Carl-Henrik HeldinArne Ostman
May 25, 2002·Seminars in Cancer Biology·Young D JungLee M Ellis
May 29, 2002·Oncogene·Jeffrey P Zwerner, William A May
Jun 5, 2003·Nature Medicine·Napoleone FerraraJennifer LeCouter
Jun 5, 2003·Cancer Cell·Kristian PietrasArne Ostman
Aug 12, 2003·Advances in Experimental Medicine and Biology·Daniel George
Sep 4, 2003·Development·Renée V Hoch, Philippe Soriano

❮ Previous
Next ❯

Citations

Feb 19, 2011·Clinical and Experimental Medicine·So-Young ChoiKyung Rae Kim
Jun 27, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Sirintip BoonjaraspinyoNarong Khuntikeo
Jun 18, 2005·Biochemical and Biophysical Research Communications·Napoleone FerraraWilliam Novotny
Aug 1, 2007·Nature Biotechnology·Farbod ShojaeiNapoleone Ferrara
Jun 25, 2010·Nature Reviews. Cancer·Alicia S ChungNapoleone Ferrara
Jul 18, 2008·Proceedings of the National Academy of Sciences of the United States of America·Frank KuhnertCalvin J Kuo
Jul 8, 2009·Proceedings of the National Academy of Sciences of the United States of America·Soo-Young KangRandolph S Watnick
Jan 13, 2005·Rheumatology·Christopher D BuckleyKarim Raza
Aug 13, 2008·Current Opinion in Hematology·Janusz RakJoanne Yu
Oct 7, 2008·The Cancer Journal·John F de Groot, Wai Kwan Alfred Yung
Apr 5, 2005·Genes & Development·Kaisa LehtiStephen J Weiss
May 17, 2008·Genes & Development·Johanna AndraeChrister Betsholtz
Oct 21, 2006·Annual Review of Medicine·Napoleone FerraraRobert Kim
Aug 30, 2008·American Journal of Physiology. Lung Cellular and Molecular Physiology·James WestKaren Fagan
Aug 7, 2012·Genes & Cancer·Sylvia Vong, Raghu Kalluri
Aug 7, 2007·International Journal of Hematology·Brett HallFrank Marini
Sep 2, 2011·Chinese Journal of Cancer·Kun-Wei LiuShi-Yuan Cheng
Jan 16, 2014·BMC Veterinary Research·Evan T MariottiGwendolen Lorch
Dec 15, 2006·Proceedings of the National Academy of Sciences of the United States of America·Robert J PelhamDavid Botstein
Jul 16, 2011·Annual Review of Cell and Developmental Biology·Alicia S Chung, Napoleone Ferrara
May 8, 2014·Journal of Neuro-oncology·Mohamed A HamzaJohn F DeGroot
Sep 4, 2008·Cell and Tissue Research·Yongping Crawford, Napoleone Ferrara
May 10, 2015·Expert Opinion on Therapeutic Targets·Stamatios TheocharisJerzy Klijanienko
Oct 27, 2015·Biomolecules·Alvaro Valin, José L Pablos
Oct 18, 2011·Expert Review of Anticancer Therapy·Collin Blakely, Thierry Jahan
Feb 4, 2009·The Journal of Cell Biology·R Grant RoweStephen J Weiss
Aug 21, 2015·Expert Opinion on Investigational Drugs·Nisha Mohindra, Mark Agulnik
Jul 12, 2005·Expert Opinion on Investigational Drugs·Jennifer S Isaacs
Dec 8, 2006·Expert Opinion on Biological Therapy·Germaine Fuh

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arterial-Venous in Development & Disease

Arterial-venous development may play a crucial role in cardiovascular diseases. Here is the latest research.

Angiogenesis Inhibitors to Treat Cancer

Cancer treatments including angiogenesis inhibitors prevent tumor cells from receiving nutrients and oxygen. Here is the latest research on angiogenesis inhibitors for the treatment of cancer.