Mechanism of lymph node metastasis in prostate cancer

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Bibliography

• 1  Brower V: Researchers tackle metastasis, cancer’s last frontier. J. Natl Cancer Inst.99(2),109–111 (2007).
  MedlineGoogle Scholar
• 2  Alitalo K, Carmeliet P: Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell1(3),219–227 (2002).▪▪ Discusses the contribution of tumor lymphatics to lymph node and distant metastasis very elegantly.
  Medline CASGoogle Scholar
• 3  Sleeman J, Schmid A, Thiele W: Tumor lymphatics. Semin. Cancer Biol.19(5),285–297 (2009).▪▪ Discusses the contribution of tumor lymphatics to lymph node and distant metastasis very elegantly.
  Medline CASGoogle Scholar
• 4  Sleeman JP, Thiele W: Tumor metastasis and the lymphatic vasculature. Int. J. Cancer125(12),2747–2756 (2009).
  Medline CASGoogle Scholar
• 5  Karkkainen MJ, Makinen T, Alitalo K: Lymphatic endothelium: a new frontier of metastasis research. Nat. Cell Biol.4(1),E2–E5 (2002).
  Medline CASGoogle Scholar
• 6  Pepper MS: Lymphangiogenesis and tumor metastasis: myth or reality? Clin. Cancer Res.7(3),462–468 (2001).
  Medline CASGoogle Scholar
• 7  Cai T, Nesi G, Tinacci G et al.: Clinical importance of lymph node density in predicting outcome of prostate cancer patients. J. Surg. Res (2009) (Epub ahead of print).▪ Describes the prognostic significance of lymph node metastasis in prostate cancer.
  Google Scholar
• 8  Cheng L, Zincke H, Blute ML, Bergstralh EJ, Scherer B, Bostwick DG: Risk of prostate carcinoma death in patients with lymph node metastasis. Cancer91(1),66–73 (2001).▪ Describes the prognostic significance of lymph node metastasis in prostate cancer.
  Medline CASGoogle Scholar
• 9  Da Pozzo LF, Cozzarini C, Briganti A et al.: Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur. Urol.55(5),1003–1011 (2009).
  MedlineGoogle Scholar
• 10  Burkhard FC, Studer UE: Regional lymph node staging in prostate cancer: prognostic and therapeutic implications. Surg. Oncol.18(3),213–218 (2009).
  MedlineGoogle Scholar
• 11  Briganti A, Blute ML, Eastham JH et al.: Pelvic lymph node dissection in prostate cancer. Eur. Urol.55(6),1251–1265 (2009).
  MedlineGoogle Scholar
• 12  Briganti A, Karnes JR, Da Pozzo LF et al.: Two positive nodes represent a significant cut-off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur. Urol.55(2),261–270 (2009).▪ Describes the prognostic significance of lymph node metastasis in prostate cancer.
  MedlineGoogle Scholar
• 13  Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R: Tumour-induced immune modulation of sentinel lymph nodes. Nat. Rev. Immunol.6(9),659–670 (2006).
  Medline CASGoogle Scholar
• 14  Huang RR, Wen DR, Guo J et al.: Selective modulation of paracortical dendritic cells and T-lymphocytes in breast cancer sentinel lymph nodes. Breast J.6(4),225–232 (2000).
  MedlineGoogle Scholar
• 15  Tammela T, Petrova TV, Alitalo K: Molecular lymphangiogenesis: new players. Trends Cell Biol.15(8),434–441 (2005).
  Medline CASGoogle Scholar
• 16  Alitalo K, Tammela T, Petrova TV: Lymphangiogenesis in development and human disease. Nature438(7070),946–953 (2005).
  Medline CASGoogle Scholar
• 17  Stacker SA, Baldwin ME, Achen MG: The role of tumor lymphangiogenesis in metastatic spread. FASEB J.16(9),922–934 (2002).
  Medline CASGoogle Scholar
• 18  Bolenz C, Fernandez MI, Tilki D et al.: The role of lymphangiogenesis in lymphatic tumour spread of urological cancers. BJU Int.104(5),592–597 (2009).
  MedlineGoogle Scholar
• 19  Karkkainen MJ, Haiko P, Sainio K et al.: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol.5(1),74–80 (2004).
  Medline CASGoogle Scholar
• 20  Dvorak HF: VPF/VEGF and the angiogenic response. Semin. Perinatol.24(1),75–78 (2000).
  Medline CASGoogle Scholar
• 21  Karpanen T, Egeblad M, Karkkainen MJ et al.: Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res.61(5),1786–1790 (2001).
  Medline CASGoogle Scholar
• 22  Stacker SA, Caesar C, Baldwin ME et al.: VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat. Med.7(2),186–191 (2001).
  Medline CASGoogle Scholar
• 23  Achen MG, Stacker SA: Molecular control of lymphatic metastasis. Ann. NY Acad. Sci.1131,225–234 (2008).
  Medline CASGoogle Scholar
• 24  Achen MG, Jeltsch M, Kukk E et al.: Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl Acad. Sci. USA95(2),548–553 (1998).
  Medline CASGoogle Scholar
• 25  Mandriota SJ, Jussila L, Jeltsch M et al.: Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J.20(4),672–682 (2001).
  Medline CASGoogle Scholar
• 26  Joukov V, Pajusola K, Kaipainen A et al.: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J.15(7),1751 (1996).
  Medline CASGoogle Scholar
• 27  Kaipainen A, Korhonen J, Mustonen T et al.: Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl Acad. Sci. USA92(8),3566–3570 (1995).
  Medline CASGoogle Scholar
• 28  Kukk E, Lymboussaki A, Taira S et al.: VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development122(12),3829–3837 (1996).
  Medline CASGoogle Scholar
• 29  He Y, Rajantie I, Pajusola K et al.: 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.65(11),4739–4746 (2005).
  Medline CASGoogle Scholar
• 30  Karpanen T, Heckman CA, Keskitalo S et al.: Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J.20(9),1462–1472 (2006).
  Medline CASGoogle Scholar
• 31  Caunt M, Mak J, Liang WC et al.: Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell13(4),331–342 (2008).
  Medline CASGoogle Scholar
• 32  Su JL, Yang PC, Shih JY et al.: The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell9(3),209–223 (2006).
  Medline CASGoogle Scholar
• 33  Muders MH, Zhang H, Wang E, Tindall DJ, Datta K: Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1. Cancer Res.69(15),6042–6048 (2009).
  Medline CASGoogle Scholar
• 34  Nagy JA, Vasile E, Feng D et al.: Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med.196(11),1497–1506 (2002).
  Medline CASGoogle Scholar
• 35  Bjorndahl MA, Cao R, Burton JB et al.: Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res.65(20),9261–9268 (2005).
  MedlineGoogle Scholar
• 36  Lohela M, Helotera H, Haiko P, Dumont DJ, Alitalo K: Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues. Am. J. Pathol.173(6),1891–1901 (2008).
  Medline CASGoogle Scholar
• 37  Benest AV, Harper SJ, Herttuala SY, Alitalo K, Bates DO: VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovasc. Res.78(2),315–323 (2008).
  Medline CASGoogle Scholar
• 38  McColl BK, Paavonen K, Karnezis T et al.: Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J.21(4),1088–1098 (2007).
  Medline CASGoogle Scholar
• 39  Scavelli C, Vacca A, Di Pietro G, Dammacco F, Ribatti D: Crosstalk between angiogenesis and lymphangiogenesis in tumor progression. Leukemia18(6),1054–1058 (2004).
  Medline CASGoogle Scholar
• 40  Laakkonen P, Waltari M, Holopainen T et al.: Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res.67(2),593–599 (2007).
  Medline CASGoogle Scholar
• 41  Gale NW, Thurston G, Hackett SF et al.: Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev. Cell3(3),411–423 (2002).
  Medline CASGoogle Scholar
• 42  Tammela T, Saaristo A, Lohela M et al.: Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood105(12),4642–4648 (2005).
  Medline CASGoogle Scholar
• 43  Cao R, Bjorndahl MA, Religa P et al.: PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell6(4),333–345 (2004).
  Medline CASGoogle Scholar
• 44  Tang Y, Zhang D, Fallavollita L, Brodt P: Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res.63(6),1166–1171 (2003).
  Medline CASGoogle Scholar
• 45  Matsuo M, Yamada S, Koizumi K, Sakurai H, Saiki I: Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells. Eur. J. Cancer43(11),1748–1754 (2007).
  Medline CASGoogle Scholar
• 46  Cao R, Bjorndahl MA, Gallego MI et al.: Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood107(9),3531–3536 (2006).
  Medline CASGoogle Scholar
• 47  Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M: Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J.24(16),2885–2895 (2005).
  Medline CASGoogle Scholar
• 48  Avraamides CJ, Garmy-Susini B, Varner JA: Integrins in angiogenesis and lymphangiogenesis. Nat. Rev. Cancer8(8),604–617 (2008).
  Medline CASGoogle Scholar
• 49  Zhang X, Groopman JE, Wang JF: Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin α5β1. J. Cell. Physiol.202(1),205–214 (2005).
  Medline CASGoogle Scholar
• 50  Furtado GC, Marinkovic T, Martin AP et al.: Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc. Natl Acad. Sci. USA104(12),5026–5031 (2007).
  Medline CASGoogle Scholar
• 51  Partanen TA, Alitalo K, Miettinen M: Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer86(11),2406–2412 (1999).
  Medline CASGoogle Scholar
• 52  Banerji S, Ni J, Wang SX et al.: LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol.144(4),789–801 (1999).
  Medline CASGoogle Scholar
• 53  Breiteneder-Geleff S, Soleiman A, Kowalski H et al.: Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol.154(2),385–394 (1999).
  Medline CASGoogle Scholar
• 54  Wigle JT, Harvey N, Detmar M et al.: An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J.21(7),1505–1513 (2002).
  Medline CASGoogle Scholar
• 55  Zeng Y, Opeskin K, Horvath LG, Sutherland RL, Williams ED: Lymphatic vessel density and lymph node metastasis in prostate cancer. Prostate65(3),222–230 (2005).
  Medline CASGoogle Scholar
• 56  Kimura Y, Watanabe M, Ohga T et al.: Vascular endothelial growth factor C expression correlates with lymphatic involvement and poor prognosis in patients with esophageal squamous cell carcinoma. Oncol. Rep.10(6),1747–1751 (2003).
  MedlineGoogle Scholar
• 57  Jia YT, Li ZX, He YT, Liang W, Yang HC, Ma HJ: Expression of vascular endothelial growth factor-C and the relationship between lymphangiogenesis and lymphatic metastasis in colorectal cancer. World J. Gastroenterol.10(22),3261–3263 (2004).
  Medline CASGoogle Scholar
• 58  Clarijs R, Schalkwijk L, Ruiter DJ, de Waal RM: Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma. Invest. Ophthalmol. Vis. Sci.42(7),1422–1428 (2001).
  Medline CASGoogle Scholar
• 59  Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO: Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res.65(21),9789–9798 (2005).
  Medline CASGoogle Scholar
• 60  Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK: Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res.64(13),4400–4404 (2004).
  Medline CASGoogle Scholar
• 61  Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK: Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res.60(16),4324–4327 (2000).
  Medline CASGoogle Scholar
• 62  Skobe M, Hawighorst T, Jackson DG et al.: Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med.7(2),192–198 (2001).
  Medline CASGoogle Scholar
• 63  Kyzas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D: Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J. Pathol.206(2),170–177 (2005).
  MedlineGoogle Scholar
• 64  Bolzoni Villaret A, Schreiber A, Facchetti F et al.: Immunostaining patterns of CD31 and podoplanin in previously untreated advanced oral/oropharyngeal cancer: prognostic implications. Head Neck (2009) (Epub ahead of print).
  Google Scholar
• 65  Hirakawa S: From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci.100(6),983–989 (2009).
  Medline CASGoogle Scholar
• 66  Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M: VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood109(3),1010–1017 (2007).
  Medline CASGoogle Scholar
• 67  Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M: VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med.201(7),1089–1099 (2005).
  Medline CASGoogle Scholar
• 68  Tsurusaki T, Kanda S, Sakai H et al.: Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br. J. Cancer80(1–2),309–313 (1999).
  Medline CASGoogle Scholar
• 69  Jennbacken K, Vallbo C, Wang W, Damber JE: Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate65(2),110–116 (2005).
  Medline CASGoogle Scholar
• 70  Zeng Y, Opeskin K, Baldwin ME et al.: Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin. Cancer Res.10(15),5137–5144 (2004).
  Medline CASGoogle Scholar
• 71  Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am. J. Pathol.143(2),401–409 (1993).
  Medline CASGoogle Scholar
• 72  Li R, Younes M, Wheeler TM et al.: Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate58(2),193–199 (2004).
  Medline CASGoogle Scholar
• 73  Trojan L, Michel MS, Rensch F, Jackson DG, Alken P, Grobholz R: Lymph and blood vessel architecture in benign and malignant prostatic tissue: lack of lymphangiogenesis in prostate carcinoma assessed with novel lymphatic marker lymphatic vessel endothelial hyaluronan receptor (LYVE-1). J. Urol.172(1),103–107 (2004).
  Medline CASGoogle Scholar
• 74  Trojan L, Rensch F, Voss M et al.: The role of the lymphatic system and its specific growth factor, vascular endothelial growth factor C, for lymphogenic metastasis in prostate cancer. BJU Int.98(4),903–906 (2006).
  Medline CASGoogle Scholar
• 75  Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M: Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod. Pathol.19(3),392–398 (2006).
  MedlineGoogle Scholar
• 76  Marks A, Sutherland DR, Bailey D et al.: Characterization and distribution of an oncofetal antigen (M2A antigen) expressed on testicular germ cell tumours. Br. J. Cancer80(3–4),569–578 (1999).
  Medline CASGoogle Scholar
• 77  Kahn HJ, Bailey D, Marks A: Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod. Pathol.15(4),434–440 (2002).
  MedlineGoogle Scholar
• 78  Kahn HJ, Marks A: A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab. Invest.82(9),1255–1257 (2002).
  MedlineGoogle Scholar
• 79  Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M: Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am. J. Pathol.166(3),913–921 (2005).
  Medline CASGoogle Scholar
• 80  Cheng L, Bishop E, Zhou H et al.: Lymphatic vessel density in radical prostatectomy specimens. Hum. Pathol.39(4),610–615 (2008).
  MedlineGoogle Scholar
• 81  Kuroda K, Horiguchi A, Asano T, Asano T, Hayakawa M: Prediction of lymphatic invasion by peritumoral lymphatic vessel density in prostate biopsy cores. Prostate68(10),1057–1063 (2008).
  MedlineGoogle Scholar
• 82  Li J, Wang E, Rinaldo F, Datta K: Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. Oncogene24(35),5510–5520 (2005).
  Medline CASGoogle Scholar
• 83  Rinaldo F, Li J, Wang E, Muders M, Datta K: RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation. Oncogene26(12),1731–1738 (2007).
  Medline CASGoogle Scholar
• 84  Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara K: Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin. Cancer Res.12(20 Pt 1),6012–6017 (2006).
  Medline CASGoogle Scholar
• 85  Zhang H, Muders MH, Li J, Rinaldo F, Tindall DJ, Datta K: Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer. Cancer Res.68(21),8770–8778 (2008).
  Medline CASGoogle Scholar
• 86  Bowen C, Bubendorf L, Voeller HJ et al.: Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res.60(21),6111–6115 (2000).
  Medline CASGoogle Scholar
• 87  Aslan G, Irer B, Tuna B, Yorukoglu K, Saatcioglu F, Celebi I: Analysis of NKX3.1 expression in prostate cancer tissues and correlation with clinicopathologic features. Pathol. Res. Pract.202(2),93–98 (2006).
  Medline CASGoogle Scholar
• 88  Asatiani E, Huang WX, Wang A et al.: Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Res.65(4),1164–1173 (2005).
  Medline CASGoogle Scholar
• 89  Prescott JL, Blok L, Tindall DJ: Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate35(1),71–80 (1998).
  Medline CASGoogle Scholar
• 90  Nadiminty N, Dutt S, Tepper C, Gao AC: Microarray analysis reveals potential target genes of NF-kB2/p52 in LNCaP prostate cancer cells. Prostate70(3),276–287 (2010).
  Medline CASGoogle Scholar
• 91  Di JM, Zhou J, Zhou XL et al.: Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-C and lymph node metastases in human prostate cancer. Arch. Med. Res.40(4),268–275 (2009).
  Medline CASGoogle Scholar
• 92  Tilki D, Irmak S, Oliveira-Ferrer L et al.: CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer. Oncogene25(36),4965–4974 (2006).
  Medline CASGoogle Scholar
• 93  Brakenhielm E, Burton JB, Johnson M et al.: Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int. J. Cancer121(10),2153–2161 (2007).
  Medline CASGoogle Scholar
• 94  Burton JB, Priceman SJ, Sung JL et al.: Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res.68(19),7828–7837 (2008).
  Medline CASGoogle Scholar
• 95  Joukov V, Kumar V, Sorsa T et al.: A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities. J. Biol. Chem.273(12),6599–6602 (1998).
  Medline CASGoogle Scholar
• 96  Zeng Y, Opeskin K, Goad J, Williams ED: Tumor-induced activation of lymphatic endothelial cells via vascular endothelial growth factor receptor-2 is critical for prostate cancer lymphatic metastasis. Cancer Res.66(19),9566–9575 (2006).
  Medline CASGoogle Scholar
• 97  Lin J, Lalani AS, Harding TC et al.: Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res.65(15),6901–6909 (2005).
  Medline CASGoogle Scholar
• 98  Tuomela J, Valta M, Seppanen J, Tarkkonen K, Vaananen HK, Harkonen P: Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors. BMC Cancer9,362 (2009).
  MedlineGoogle Scholar
• 99  Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST: Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J. Natl Cancer Inst.93(21),1638–1643 (2001).
  Medline CASGoogle Scholar
• 100  Shields JD, Emmett MS, Dunn DB et al.: Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis. Oncogene26(21),2997–3005 (2007).
  Medline CASGoogle Scholar