Reader Comments

Post a new comment on this article

More to VEGFR-1 / Flt1 than meets the eye

Posted by plosmedicine on 31 Mar 2009 at 00:10 GMT

Author: Asif Ahmed
Position: Professor of Reproductive and Vascular Biology
Institution: Department of Reproductive and Vascular Biology, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom
Submitted Date: July 12, 2007
Published Date: July 13, 2007
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

This article is a beautifully conducted study depicting a novel role of internally expressed VEGFR-1 in primary tumour cells that shows that VEGFR-1 is important to promote survival in primary tumour cells. It also confirms that the mechanism of VEGFR-1-mediated endothelial cells survival demonstrated by us (Cai et al, 2003), which the article cites, is a general phenomenon.

Unfortunately, some key historical papers are missing that highlight the role of VEGFR-1 in non-endothelial and tumour cells. Almost 10 years ago, we demonstrated that VEGFR-1 stimulated nitric oxide release to inhibit VEGFR-2-mediated cell proliferation in trophoblast (fetal) cells (Ahmed et al, 1997). This work should be cited as it established the principle that VEGFR-1 could regulate the activities of VEGFR-2, the receptor responsible for the mitogenic properties of VEGF (Waltenberger et al, 1994). Indeed, this has turned out to be a general mechanism of regulation and was confirmed by others and us in endothelial cells (Bussolati et al, 2001; Rahimi et al, 2000; Zeng et al, 2002) as well as tumor cells (Dunk and Ahmed, 2001).

ECV304 are not endothelial cells but a human bladder cancer epithelial cell line (Brown et al, 2000). In 2001, our laboratory showed that VEGFR-2-mediated mitogenesis is negatively regulated by VEGFR-1 via nitric oxide in these cells (Dunk and Ahmed, 2001). The current study in PLoS Med reinforces the view we were propagated in our article that inhibiting VEGFR-2 is not sufficient to inhibit tumour growth.

It is incumbent upon all of us to ensure that the appropriate literature is cited and due credits give to the researchers in the field. PLoS Med should be congratulated for providing a forum to clarify these types of issues. We have had a long-term interest in VEGFR-1 biology and it was a pleasure to read this article. Perhaps it is time to undertake a comprehensive review of VEGFR-1 function in biology and pathology, which we have been thinking of doing.


Ahmad S, Hewett PW, Wang P, Al-Ani B Cudmore M, Fujisawa T, Wang P, Haigh JJ, Le Noble F, Mukhopadhyay D and Ahmed A. Circ Res 2006; 99:715-22.

Ahmed A, Dunk C, Li XF, Kinnis D, and Wilkes M. Lab Invest 1997; 76: 779-791.

Brown J, Reading SJ, Jones S, Fitchett CJ, Howl J, Martin A, Longland CL, Michelangeli F, Dubrova YE, Brown CA. Lab Invest. 2000;80:37-45.

Bussolati B, Dunk CE, Grohmann M, Kontos CD, Mason J. and Ahmed A. Am J Pathol 2001; 159: 993-1008.

Cai J, Ahmad S, Jiang WG, Huang J, Kontos CD, Boulton M, Ahmed A. Diabetes 2003; 52:2959-68.

Dunk C, Ahmed A. Am J Pathol 2001; 158: 265-273.

Rahimi N, Dayanir V, Lashkari K. J Biol Chem 2000;275:16986-16992.

Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. J Biol Chem. 1994;269:26988-95.

Zeng H, Zhao D, Mukhopadhyay D. J Biol Chem 2002;277:4003-4009

No competing interests declared.