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VEGF targets the tumour cell

Key Points

  • Tumour cells express vascular endothelial growth factor (VEGF) receptors and respond to autocrine and paracrine VEGF signals.

  • VEGF signalling in tumour cells affects tumour functions independently of angiogenesis.

  • VEGF signalling in tumour cells is mediated by VEGF receptor tyrosine kinases (RTKs) and neuropilins (NRPs).

  • NRPs may be at the centre of VEGF signalling because they regulate the function of RTKs and integrins that are crucial for tumour cell function.

  • Autocrine VEGF signalling may be essential for tumour initiation because it regulates the size of the cancer stem cell pool and the self-renewal of cancer stem cells.

  • Therapeutic approaches that aim to target NRPs and VEGF RTKs on tumour cells could be useful to promote tumour regression and to diminish the probability of tumour recurrence, especially when used in combination with VEGF-specific antibodies and other modes of therapy.

Abstract

The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

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Figure 1: VEGF functions in tumours.
Figure 2: Receptor interactions that promote VEGF signalling in tumour cells, and the central role of NRPs.
Figure 3: Role of autocrine VEGF signalling in the function of cancer stem cells and tumour formation.
Figure 4: Therapeutic targeting of VEGF signalling in tumour cells.

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References

  1. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Tischer, E. et al. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem. Biophys. Res. Commun. 165, 1198–1206 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Senger, D. R., Connolly, D. T., Van de Water, L., Feder, J. & Dvorak, H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 50, 1774–1778 (1990).

    CAS  PubMed  Google Scholar 

  4. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Koch, S. & Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect. Med. 2, a006502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chung, A. S. & Ferrara, N. Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27, 563–584 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Ferrara, N. VEGF as a therapeutic target in cancer. Oncology 69 (Suppl. 3), 11–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature Rev. Cancer 8, 579–591 (2008).

    Article  CAS  Google Scholar 

  9. Senger, D. R. Vascular endothelial growth factor: much more than an angiogenesis factor. Mol. Biol. Cell 21, 377–379 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hansen, W. et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med. 209, 2001–2016 (2012). This study rigorously shows the importance of NRP1 on immune cells in regulating tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yaqoob, U. et al. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res. 72, 4047–4059 (2012). This study shows a novel role for NRP1 that is expressed on tumour myofibroblasts in regulating tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kowanetz, M. & Ferrara, N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin. Cancer Res. 12, 5018–5022 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Waldner, M. J. et al. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J. Exp. Med. 207, 2855–2868 (2010). This is a thought-provoking study showing that chronic inflammation induces VEGFR2 expression on intestinal epithelial cells and that VEGFR2 signalling is necessary for tumour growth. These findings establish an important link between inflammation and cancer that involves VEGF signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hamerlik, P. et al. Autocrine VEGF–VEGFR2–neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J. Exp. Med. 209, 507–520 (2012). This study defines the importance of autocrine VEGF signalling in the function of glioma stem cells, and it shows that this signalling can occur in an intracellular compartment, which is a result that has considerable implications for therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Goel, H. L. et al. VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-1R define a novel mechanism of aggressive prostate cancer Cancer Discov. 2, 906–921 (2012). This study shows the ability of NRP2-mediated VEGF signalling to regulate BMI1, which is a crucial stem cell factor. Importantly, this study also shows that therapeutic targeting of NRP2 results in compensatory IGF1R signalling and that combined NRP2 and IGF1R therapy can be effective.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cao, Y. et al. VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res. 72, 3912–3918 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Karkkainen, M. J. & Petrova, T. V. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19, 5598–5605 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Bates, R. C. et al. Flt-1-dependent survival characterizes the epithelial–mesenchymal transition of colonic organoids. Curr. Biol. 13, 1721–1727 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Soker, S. et al. Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype. Am. J. Pathol. 159, 651–659 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prud'homme, G. J. & Glinka, Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 3, 921–939 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Parker, M. W., Guo, H. F., Li, X., Linkugel, A. D. & Vander Kooi, C. W. Function of members of the neuropilin family as essential pleiotropic cell surface receptors. Biochemistry 51, 9437–9446 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Kolodkin, A. L. et al. Neuropilin is a semaphorin III receptor. Cell 90, 753–762 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, H., Chedotal, A., He, Z., Goodman, C. S. & Tessier-Lavigne, M. Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19, 547–559 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Winberg, M. L. et al. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95, 903–916 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi, T. et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99, 59–69 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Geretti, E., Shimizu, A. & Klagsbrun, M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 11, 31–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Parker, M. W., Xu, P., Li, X. & Vander Kooi, C. W. Structural basis for selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1. J. Biol. Chem. 287, 11082–11089 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rossignol, M., Gagnon, M. L. & Klagsbrun, M. Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 70, 211–222 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Frankel, P. et al. Chondroitin sulphate-modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas-mediated pathway. EMBO Rep. 9, 983–989 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shintani, Y. et al. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling. EMBO J. 25, 3045–3055 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zachary, I. C., Frankel, P., Evans, I. M. & Pellet-Many, C. The role of neuropilins in cell signalling. Biochem. Soc. Trans. 37, 1171–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998). This is a seminal study showing that NRP1 can function as a VEGF receptor and that it is expressed on tumour cells.

    Article  CAS  PubMed  Google Scholar 

  33. Neufeld, G., Sabag, A. D., Rabinovicz, N. & Kessler, O. Semaphorins in angiogenesis and tumor progression. Cold Spring Harb. Perspect. Med. 2, a006718 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kigel, B., Rabinowicz, N., Varshavsky, A., Kessler, O. & Neufeld, G. Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118, 4285–4296 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Neufeld, G., Kessler, O. & Herzog, Y. The interaction of neuropilin-1 and neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv. Exp. Med. Biol. 515, 81–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Bachelder, R. E. et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 61, 5736–5740 (2001).

    CAS  PubMed  Google Scholar 

  37. Perrot-Applanat, M. & Di Benedetto, M. Autocrine functions of VEGF in breast tumor cells: adhesion, survival, migration and invasion. Cell Adh. Migr. 6, 547–553 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Goel, H. L. et al. GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol. Med. 5, 488–508 (2013). This study provides the best example so far of how NRP2-mediated VEGF signalling can promote tumour initiation through a mechanism that involves the integrin-mediated regulation of GLI1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, J. et al. Blockade of VEGF-A suppresses tumor growth via inhibition of autocrine signaling through FAK and AKT. Cancer Lett. 318, 221–225 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Beck, B. et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478, 399–403 (2011). This is a seminal study that establishes the importance of NRP1-mediated autocrine VEGF signalling in regulating the size of the cancer stem cell pool and the stemness of these cells.

    Article  CAS  PubMed  Google Scholar 

  41. Lichtenberger, B. M. et al. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140, 268–279 (2010). This is a study that uses a transgenic mouse model to rigorously show the importance of autocrine VEGF signalling during the genesis of squamous carcinoma.

    Article  CAS  PubMed  Google Scholar 

  42. Matsuura, M. et al. Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells. Am. J. Pathol. 175, 1709–1721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schoeffner, D. J. et al. VEGF contributes to mammary tumor growth in transgenic mice through paracrine and autocrine mechanisms. Lab Invest. 85, 608–623 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Schmidt, T. et al. Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1+ leukemia. Cancer Cell 19, 740–753 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Senger, D. R. & Van De Water, L. VEGF expression by epithelial and stromal cell compartments: resolving a controversy. Am. J. Pathol. 157, 1–3 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mak, P. et al. ERβ impedes prostate cancer EMT by destabilizing HIF-1α and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 17, 319–332 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genet. 40, 499–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Wanami, L. S., Chen, H. Y., Peiro, S., Garcia de Herreros, A. & Bachelder, R. E. Vascular endothelial growth factor-A stimulates Snail expression in breast tumor cells: implications for tumor progression. Exp. Cell Res. 314, 2448–2453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mimeault, M. & Batra, S. K. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J. Cell. Mol. Med. 17, 30–54 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Grugel, S., Finkenzeller, G., Weindel, K., Barleon, B. & Marme, D. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J. Biol. Chem. 270, 25915–25919 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Mak, P., Chang, C., Pursell, B. & Mercurio, A. M. Estrogen receptor-β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. Proc. Natl Acad. Sci. USA 110, 4708–4713 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hillman, R. T. et al. Neuropilins are positive regulators of Hedgehog signal transduction. Genes Dev. 25, 2333–2346 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cao, Y. et al. Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res. 68, 8667–8672 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lin, F. J. et al. Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J. Clin. Invest. 120, 1694–1707 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Qin, J. et al. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature 493, 236–240 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. You, L. R. et al. Suppression of notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Williams, C. K., Li, J. L., Murga, M., Harris, A. L. & Tosato, G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107, 931–939 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sorensen, I., Adams, R. H. & Gossler, A. DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 113, 5680–5688 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Lee, T. H. et al. Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med. 4, e186 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nakayama, M. & Berger, P. Coordination of VEGF receptor trafficking and signaling by coreceptors. Exp. Cell Res. 319, 1340–1347 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012). This is a thought-provoking study showing that VEGF–VEGR2 signalling inhibits the HGF-mediated invasion of glioblastoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Matsushita, A., Gotze, T. & Korc, M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 67, 10309–10316 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Hu, B. et al. Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene 26, 5577–5586 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rizzolio, S. et al. Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res. 72, 5801–5811 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Grandclement, C. et al. Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS ONE 6, e20444 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Glinka, Y. Stoilova, S., Mohammed, N. & Prud'homme, G. J. Neuropilin-1 exerts co-receptor function for TGF-β-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-β. Carcinogenesis 32, 613–621 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Migdal, M. et al. Neuropilin-1 is a placenta growth factor-2 receptor. J. Biol. Chem. 273, 22272–22278 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. West, D. C. et al. Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J. Biol. Chem. 280, 13457–13464 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Glinka, Y. & Prud'homme, G. J. Neuropilin-1 is a receptor for transforming growth factor β-1, activates its latent form, and promotes regulatory T cell activity. J. Leukoc. Biol. 84, 302–310 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Banerjee, S. et al. Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol. Carcinog. 45, 871–880 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Byzova, T. V. et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol. Cell 6, 851–860 (2000). This study provided the first indication that VEGF signalling can regulate integrin activation in tumour cells.

    CAS  PubMed  Google Scholar 

  72. Soldi, R. et al. Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J. 18, 882–892 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fukasawa, M., Matsushita, A. & Korc, M. Neuropilin-1 interacts with integrin β1 and modulates pancreatic cancer cell growth, survival and invasion. Cancer Biol. Ther. 6, 1173–1180 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Goel, H. L., Pursell, B., Standley, C., Fogarty, K. & Mercurio, A. M. Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling. J. Cell Sci. 125, 497–506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Herzog, B., Pellet-Many, C., Britton, G., Hartzoulakis, B. & Zachary, I. C. VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation. Mol. Biol. Cell 22, 2766–2776 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, T. T. et al. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J. Cell Biol. 188, 595–609 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zachary, I. C. How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns. Biochem. Soc. Trans. 39, 1583–1591 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. De Vries, L., Lou, X., Zhao, G., Zheng, B. & Farquhar, M. G. GIPC, a PDZ domain containing protein, interacts specifically with the C terminus of RGS-GAIP. Proc. Natl Acad. Sci. USA 95, 12340–12345 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Katoh, M. Functional proteomics, human genetics and cancer biology of GIPC family members. Exp. Mol. Med. 45, e26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Snuderl, M. et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152, 1065–1076 (2013). This is an important study that establishes the potential for treating medulloblastoma by antibody-mediated targeting of PLGF and NRP1 on tumour cells and by negating the contribution of VEGFR1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Valdembri, D. et al. Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biol. 7, e25 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Barr, M. P., Bouchier-Hayes, D. J. & Harmey, J. J. Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia. Int. J. Oncol. 32, 41–48 (2008).

    CAS  PubMed  Google Scholar 

  83. Parikh, A. A. et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am. J. Pathol. 164, 2139–2151 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Parikh, A. A. et al. Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma. Cancer 98, 720–729 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Samuel, S. et al. Neuropilin-2 mediated β-catenin signaling and survival in human gastro-intestinal cancer cell lines. PLoS ONE 6, e23208 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Spannuth, W. A. et al. Functional significance of VEGFR-2 on ovarian cancer cells. Int. J. Cancer 124, 1045–1053 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Takahashi, Y., Kitadai, Y., Bucana, C. D., Cleary, K. R. & Ellis, L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 55, 3964–3968 (1995).

    CAS  PubMed  Google Scholar 

  88. Wey, J. S. et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104, 427–438 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Wey, J. S. et al. Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells. Br. J. Cancer 93, 233–241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dallas, N. A. et al. Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma. Clin. Cancer Res. 14, 8052–8060 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Itakura, J., Ishiwata, T., Shen, B., Kornmann, M. & Korc, M. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int. J. Cancer 85, 27–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Fan, F. et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24, 2647–2653 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Stanton, M. J. et al. Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Res. 73, 160–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Philip, B., Ito, K., Moreno-Sanchez, R. & Ralph, S. J. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34, 1699–1707 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Lathia, J. D. et al. Integrin α 6 regulates glioblastoma stem cells. Cell Stem Cell 6, 421–432 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cariati, M. et al. α-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int. J. Cancer 122, 298–304 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Liu, S. et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66, 6063–6071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lukacs, R. U., Memarzadeh, S., Wu, H. & Witte, O. N. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 7, 682–693.

  100. Maru, Y., Yamaguchi, S. & Shibuya, M. Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials. Oncogene 16, 2585–2595 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926–940 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Singh, R. P., Franke, K. & Wielockx, B. Hypoxia-mediated regulation of stem cell fate. High Alt. Med. Biol. 13, 162–168 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Shibuya, M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 153, 13–19 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Bottsford-Miller, J. N., Coleman, R. L. & Sood, A. K. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J. Clin. Oncol. 30, 4026–4034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lambrechts, D., Lenz, H. J., de Haas, S., Carmeliet, P. & Scherer, S. J. Markers of response for the antiangiogenic agent bevacizumab. J. Clin. Oncol. 31, 1219–1230 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Geretti, E. et al. A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol. Cancer Res. 8, 1063–1073 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pan, Q. et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11, 53–67 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Van Cutsem, E. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized Phase III trial. J. Clin. Oncol. 30, 2119–2127 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Jubb, A. M. et al. Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin. Cancer Res. 17, 372–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Caunt, M. et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13, 331–342 (2008). References 108 and 111 establish the efficacy of using function-blocking antibodies to inhibit NRP1 and NRP2 with minimal side effects.

    Article  CAS  PubMed  Google Scholar 

  112. Liang, W. C. et al. Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J. Mol. Biol. 366, 815–829 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Gray, M. J. et al. Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J. Natl Cancer Inst. 100, 109–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Nasarre, C. et al. Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene 29, 2381–2392 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Xin, Y. et al. Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans. Pharm. Res. 29, 2512–2521 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Weekes, C. D. et al. A Phase 1b study for MNRP1685A(anti-NRP1) administered intravenously with bevacizumab with or without paclitaxel to patients with advanced solid tumors. J. Clin. Oncol. Abstr. 29, 3050 (2011). References 115 and 116 raise concerns about using NRP-specific antibody therapy, and these studies show the need to develop more targeted approaches.

    Article  Google Scholar 

  117. Roth, L. et al. Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31, 3754–3763 (2012). This study describes a novel approach to deliver drugs to tumour cells using NRPs.

    Article  CAS  PubMed  Google Scholar 

  118. Heffelfinger, S. C. et al. Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation. Lab Invest. 84, 989–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Adham, S. A., Sher, I. & Coomber, B. L. Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. Lab Invest. 90, 709–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Fukasawa, M. & Korc, M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin. Cancer Res. 10, 3327–3332 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009). This study shows that conditional deletion of VEGFA in pancreatic carcinoma cells increased tumour invasiveness, which is a result that provides a note of caution because VEGFA loss should disrupt autocrine VEGF signalling and decrease tumour invasiveness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Galdiero, M. R. et al. Tumor associated macrophages and neutrophils in cancer. Immunobiology 218, 1402–1410 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Gaur, P. et al. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin. Cancer Res. 15, 6763–6770 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Bender, R. J. & Mac Gabhann, F. Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer. PLoS ONE 8, e61788 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Driessens, M. H. et al. Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr. Biol. 11, 339–344 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Wong, O. G. et al. Plexin-B1 mutations in prostate cancer. Proc. Natl Acad. Sci. USA 104, 19040–19045 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Worzfeld, T. et al. ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J. Clin. Invest. 122, 1296–1305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Xia, G. et al. Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer. J. Urol. 175, 1245–1252 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Sato, K. et al. Expression of vascular endothelial growth factor gene and its receptor (flt-1) gene in urinary bladder cancer. Tohoku J. Exp. Med. 185, 173–184 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Hlobilkova, A. et al. Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression. Neoplasma 56, 284–290 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Knizetova, P. et al. Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay. Cell Cycle 7, 2553–2561 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. de Jong, J. S., van Diest, P. J., van der Valk, P. & Baak, J. P. Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops. J. Pathol. 184, 44–52 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Mylona, E. et al. The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol. Oncol. 104, 557–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Ghosh, S. et al. High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum. Pathol. 39, 1835–1843 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wei, S. C. et al. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 54, 666–672 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ozdemir, F. et al. The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer. J. Exp. Clin. Cancer Res. 25, 83–88 (2006).

    CAS  PubMed  Google Scholar 

  138. Kyzas, P. A., Cunha, I. W. & Ioannidis, J. P. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin. Cancer Res. 11, 1434–1440 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Riedel, F. et al. Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur. Arch. Otorhinolaryngol. 257, 332–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Carrillo de Santa Pau, E. et al. Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer 115, 1701–1712 (2009).

    Article  PubMed  Google Scholar 

  141. Decaussin, M. et al. Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival. J. Pathol. 188, 369–377 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Seto, T. et al. Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer. Lung Cancer 53, 91–96 (2006).

    Article  PubMed  Google Scholar 

  143. Lantuejoul, S. et al. Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines. J. Pathol. 200, 336–347 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Strizzi, L. et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J. Pathol. 193, 468–475 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Padro, T. et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16, 1302–1310 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Chen, H., Ye, D., Xie, X., Chen, B. & Lu, W. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol. Oncol. 94, 630–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Hall, G. H. et al. Neuropilin-1 and VEGF correlate with somatostatin expression and microvessel density in ovarian tumours. Int. J. Oncol. 27, 1283–1288 (2005).

    CAS  PubMed  Google Scholar 

  148. von Marschall, Z. et al. De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. Gastroenterology 119, 1358–1372 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Kollermann, J. & Helpap, B. Expression of vascular endothelial growth factor (VEGF) and VEGF receptor Flk-1 in benign, premalignant, and malignant prostate tissue. Am. J. Clin. Pathol. 116, 115–121 (2001).

    Article  CAS  PubMed  Google Scholar 

  150. Latil, A. et al. VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms. Int. J. Cancer 89, 167–171 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Yacoub, M. et al. Differential expression of the semaphorin 3A pathway in prostatic cancer. Histopathology 55, 392–398 (2009).

    Article  PubMed  Google Scholar 

  152. Gunningham, S. P. et al. VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. J. Pathol. 193, 325–332 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Su, J. L. et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 9, 209–223 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Van Trappen, P. O. et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J. Pathol. 201, 544–554 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Hashimoto, I. et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br. J. Cancer 85, 93–97 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Witte, D., Thomas, A., Ali, N., Carlson, N. & Younes, M. Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res. 22, 1463–1466 (2002).

    CAS  PubMed  Google Scholar 

  157. Akagi, K. et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br. J. Cancer 83, 887–891 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Yonemura, Y. et al. Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur. J. Cancer 37, 918–923 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Neuchrist, C. et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 25, 464–474 (2003).

    Article  PubMed  Google Scholar 

  160. Kojima, H. et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 104, 1668–1677 (2005).

    Article  CAS  PubMed  Google Scholar 

  161. Juttner, S. et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J. Clin. Oncol. 24, 228–240 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Parr, C., Watkins, G., Boulton, M., Cai, J. & Jiang, W. G. Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur. J. Cancer 41, 2819–2827 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Chen, C. N. et al. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett. 213, 73–82 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Ho, M. C. et al. Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma. Cancer Lett. 250, 237–249 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Wu, Y. et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int. J. Cancer 119, 1519–1529 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Lalla, R. V., Boisoneau, D. S., Spiro, J. D. & Kreutzer, D. L. Expression of vascular endothelial growth factor receptors on tumor cells in head and neck squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 129, 882–888 (2003).

    Article  PubMed  Google Scholar 

  167. Straume, O. & Akslen, L. A. Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. Angiogenesis 6, 295–301 (2003).

    Article  CAS  PubMed  Google Scholar 

  168. Gockel, I. et al. Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. Oncol. Rep. 20, 845–850 (2008).

    CAS  PubMed  Google Scholar 

  169. Jackson, M. W. et al. A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res. 62, 854–859 (2002).

    CAS  PubMed  Google Scholar 

  170. Nobusawa, S., Stawski, R., Kim, Y. H., Nakazato, Y. & Ohgaki, H. Amplification of the PDGFRA, KIT and KDR genes in glioblastoma: a population-based study. Neuropathology 31, 583–588 (2011).

    Article  PubMed  Google Scholar 

  171. Puputti, M. et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol. Cancer Res. 4, 927–934 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Nakopoulou, L. et al. Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. Hum. Pathol. 33, 863–870 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Longatto-Filho, A. et al. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer 9, 212 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Giatromanolaki, A. et al. Activated VEGFR2/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer. Eur. J. Clin. Invest. 37, 878–886 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Giatromanolaki, A. et al. Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis. Mod. Pathol. 19, 701–707 (2006).

    Article  CAS  PubMed  Google Scholar 

  176. Neuchrist, C. et al. Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck. Laryngoscope 111, 1834–1841 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Huang, J. et al. Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J. Clin. Pathol. 64, 343–348 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Yang, F. et al. Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy. Cancer Res. 71, 5512–5521 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Giatromanolaki, A. et al. Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res. 30, 2831–2836 (2010).

    CAS  PubMed  Google Scholar 

  180. Badalian, G., Derecskei, K., Szendroi, A., Szendroi, M. & Timar, J. EGFR and VEGFR2 protein expressions in bone metastases of clear cell renal cancer. Anticancer Res. 27, 889–894 (2007).

    CAS  PubMed  Google Scholar 

  181. Sato, H. & Takeda, Y. VEGFR2 expression and relationship between tumor neovascularization and histologic characteristics in oral squamous cell carcinoma. J. Oral Sci. 51, 551–557 (2009).

    Article  PubMed  Google Scholar 

  182. Rodriguez-Antona, C. et al. Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. Endocr. Relat. Cancer 17, 7–16 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Broholm, H. & Laursen, H. Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. APMIS 112, 257–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  184. Ding, H. et al. Expression and regulation of neuropilin-1 in human astrocytomas. Int. J. Cancer 88, 584–592 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Jubb, A. M. et al. Neuropilin-1 expression in cancer and development. J. Pathol. 226, 50–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Staton, C. A. et al. Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology 59, 274–282 (2011).

    Article  PubMed  Google Scholar 

  187. Ochiumi, T. et al. Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer. Int. J. Oncol. 29, 105–116 (2006).

    CAS  PubMed  Google Scholar 

  188. Hansel, D. E. et al. Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am. J. Surg. Pathol. 28, 347–356 (2004).

    Article  PubMed  Google Scholar 

  189. Kawakami, T. et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer 95, 2196–2201 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Osada, R. et al. Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. Hum. Pathol. 37, 1414–1425 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Baba, T. et al. Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol. Oncol. 105, 703–711 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Muller, M. W. et al. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int. J. Cancer 121, 2421–2433 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Li, M. et al. Pancreatic carcinoma cells express neuropilins and vascular endothelial growth factor, but not vascular endothelial growth factor receptors. Cancer 101, 2341–2350 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Fukahi, K., Fukasawa, M., Neufeld, G., Itakura, J. & Korc, M. Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells. Clin. Cancer Res. 10, 581–590 (2004).

    Article  CAS  PubMed  Google Scholar 

  195. Vanveldhuizen, P. J. et al. Differential expression of neuropilin-1 in malignant and benign prostatic stromal tissue. Oncol. Rep. 10, 1067–1071 (2003).

    CAS  PubMed  Google Scholar 

  196. Sanchez-Carbayo, M. et al. Gene discovery in bladder cancer progression using cDNA microarrays. Am. J. Pathol. 163, 505–516 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Jubb, A. M. et al. Neuropilin-2 expression in cancer. Histopathology 61, 340–349 (2012).

    Article  PubMed  Google Scholar 

  198. Yasuoka, H. et al. Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression. BMC Cancer 9, 220 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Rushing, E. C. et al. Neuropilin-2: a novel biomarker for malignant melanoma? Hum. Pathol. 43, 381–389 (2012).

    Article  CAS  PubMed  Google Scholar 

  200. Cao, Y. et al. Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. Cancer Res. 73, 4579–4590 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors' laboratory is supported by US National Institutes of Health (NIH) grants CA168464 and CA159856, and by a US Department of Defense prostate cancer grant W81XWH-12-1-0308.

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Glossary

Integrins

A family of more than 20 heterodimeric cell surface extracellular matrix (ECM) receptors. Integrins connect the ECM to the cytoskeleton and can transmit signalling information bidirectionally.

Plexins

A large family of transmembrane proteins that share homology in their extracellular domains with the MET receptor and semaphorins.

Epithelial–mesenchymal transition

(EMT). A conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Hypoxia-inducible factor

(HIF). A dimeric transcription factor that is formed of α- and β-subunits and that is involved in the hypoxia-sensitive regulation of numerous genes, including glycolytic enzymes, glucose transporters and angiogenic factors.

Focal adhesions

Dynamic, macromolecular protein complexes that link the extracellular matrix to the actin cytoskeleton through integrins.

PDZ-binding domain

(PSD95, DLG and ZO1-binding domain). A structural, protein–protein interaction domain, which is 80–90 amino acids in length, that often functions as a scaffold for signalling complexes and/or as a cytoskeletal anchor for transmembrane proteins.

Immunoreceptor tyrosine-based activation motif

(ITAM). A motif (YXXL or YXXI) that can be phosphorylated in response to receptor ligation and that functions as a docking site for other proteins involved in signal transduction.

Autophagy

A cellular response in which the cell metabolizes its own contents and organelles to maintain energy production. Although such a process can eventually result in cell death, it can also be used to maintain cell survival in conditions of limiting nutrients.

CD133

A cell-surface glycoprotein, which is also known as Prominin 1, that can be used as a marker for some cancer stem cells.

Polycomb group

Proteins that were first described in Drosophila melanogaster and that are required for normal development. They work in multiprotein complexes that are called Polycomb repressive complexes, which establish regions of chromatin in which gene expression is repressed.

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Goel, H., Mercurio, A. VEGF targets the tumour cell. Nat Rev Cancer 13, 871–882 (2013). https://doi.org/10.1038/nrc3627

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