Plexin D1

To grow beyond the size of 2-3 mm3 a tumor needs to arrange its own vasculature in order to supply the tumor cells with their essential nutrients (2-4). Specifically targeting the process of angiogenesis has therefore been a promising strategy for anti-cancer therapies. Even though promising results were obtained in animal tumor models, translating this approach to the clinic has proven to be difficult (5-7). Research has shown that certain tumors are able to shift towards angiogenesis-independent growth upon anti-angiogenesis therapy (8-10). Especially metastases, which are bloodborne and as a consequence generally grow in organs with a high vessel density, are able to target and utilize the existing vascular bed (vessel co-option) and thereby provide access to essential nutrients (8, 11-12). These results suggest that a combination therapy targeting both angiogenesis as well as co-option might prove a more effective treatment strategy.

Interestingly, the cell surface receptor plexin D1 has been shown to be expressed on tumor cells as well as the tumor vasculature in a mouse model of brain metastasis (13). We believe this receptor is a unique candidate for tumor targeting therapies as plexin D1 was shown to be expressed at high levels in the tumor cells as well as its vessels, but not in unaffected brain vessels.

2. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 2004, 15:275-286

3. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182-1186

4. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995, 1:27-31

5. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley AL, Hennequin LF. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002, 62:4645-4655

6. Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997, 390:404-407

7. Eichhorn ME, Strieth S, Dellian M. Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives. Drug Resist Updat 2004, 7:125-138

8. Leenders WP, Kusters B, de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 2002, 9:83-87

9. Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den HE, Goovaerts G, Dirix LY, Van Marck E. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol 2001, 195:336-342

10. Dome B, Paku S, Somlai B, Timar J. Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J Pathol 2002, 197:355-362

11. Kusters B, Leenders WP, Wesseling P, Smits D, Verrijp K, Ruiter DJ, Peters JP, van der Kogel AJ, de Waal RM. Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res 2002, 62:341-345

12. Kusters B, de Waal RM, Wesseling P, Verrijp K, Maass C, Heerschap A, Barentsz JO, Sweep F, Ruiter DJ, Leenders WP. Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma. Cancer Res 2003, 63:5408-5413

13. Roodink I, Raats J, van der Zwaag B, Verrijp K, Kusters B, van Bokhoven H, Linkels M, de Waal RM, Leenders WP. Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy? Cancer Res 2005, 65:8317-8323