Top

BMC Cancer

Published in:

Open Access 01-12-2009 | Research article

Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors

Authors: Johanna Tuomela, Maija Valta, Jani Seppänen, Kati Tarkkonen, H Kalervo Väänänen, Pirkko Härkönen

Published in: BMC Cancer | Issue 1/2009

Abstract

Background

Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood.

Methods

We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice.

Results

VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC-3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001).

Conclusion

The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.

Available only for authorised users

Bader P, Burkhard FC, Markwalder R, Studer UE: Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure?. J Urol. 2003, 169 (3): 849-854. 10.1097/01.ju.0000049032.38743.c7.CrossRefPubMed

Jacobs SC: Spread of prostatic cancer to bone. Urology. 1983, 21 (4): 337-344. 10.1016/0090-4295(83)90147-4.CrossRefPubMed

Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006, 12 (20 Pt 2): 6243-6249. 10.1158/1078-0432.CCR-06-0931.CrossRef

Smith JA, Seaman JP, Gleidman JB, Middleton RG: Pelvic lymph node metastasis from prostatic cancer: influence of tumor grade and stage in 452 consecutive patients. J Urol. 1983, 130 (5): 290-292.PubMed

Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ: Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000, 31 (5): 578-583. 10.1053/hp.2000.6698.CrossRefPubMed

Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K: Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997, 16 (13): 3898-3911. 10.1093/emboj/16.13.3898.CrossRefPubMedPubMedCentral

Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K: Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001, 20 (17): 4762-4773. 10.1093/emboj/20.17.4762.CrossRefPubMedPubMedCentral

Tammela T, Enholm B, Alitalo K, Paavonen K: The biology of vascular endothelial growth factors. Cardiovasc Res. 2005, 65 (3): 550-563. 10.1016/j.cardiores.2004.12.002.CrossRefPubMed

Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: 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. 1996, 15 (7): 1751-PubMedPubMedCentral

10.

Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, Sonoo H: Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res. 1999, 90 (9): 977-981.CrossRefPubMed

11.

Nakamura Y, Yasuoka H, Tsujimoto M, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K: Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat. 2005, 91 (2): 125-132. 10.1007/s10549-004-5783-x.CrossRefPubMed

12.

Choi WW, Lewis MM, Lawson D, Yin-Goen Q, Birdsong GG, Cotsonis GA, Cohen C, Young AN: Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005, 18 (1): 143-152. 10.1038/modpathol.3800253.CrossRefPubMed

13.

Li R, Younes M, Wheeler TM, Scardino P, Ohori M, Frolov A, Ayala G: Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate. 2004, 58 (2): 193-199. 10.1002/pros.10321.CrossRefPubMed

14.

Tsurusaki T, Kanda S, Sakai H, Kanetake H, Saito Y, Alitalo K, Koji T: Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer. 1999, 80 (1-2): 309-313. 10.1038/sj.bjc.6690356.CrossRefPubMedPubMedCentral

15.

Zeng Y, Opeskin K, Baldwin ME, Horvath LG, Achen MG, Stacker SA, Sutherland RL, Williams ED: Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res. 2004, 10 (15): 5137-5144. 10.1158/1078-0432.CCR-03-0434.CrossRefPubMed

16.

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. Prostate. 2005, 65 (2): 110-116. 10.1002/pros.20276.CrossRefPubMed

17.

Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M: Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001, 7 (2): 192-198. 10.1038/84643.CrossRefPubMed

18.

Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS: Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001, 20 (4): 672-682. 10.1093/emboj/20.4.672.CrossRefPubMedPubMedCentral

19.

Mattila MM, Ruohola JK, Karpanen T, Jackson DG, Alitalo K, Harkonen PL: VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int J Cancer. 2002, 98 (6): 946-951. 10.1002/ijc.10283.CrossRefPubMed

20.

Brakenhielm E, Burton JB, Johnson M, Chavarria N, Morizono K, Chen I, Alitalo K, Wu L: Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer. 2007, 121 (10): 2153-2161. 10.1002/ijc.22900.CrossRefPubMedPubMedCentral

21.

Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, Alitalo K, Wu L: Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 2008, 68 (19): 7828-7837. 10.1158/0008-5472.CAN-08-1488.CrossRefPubMedPubMedCentral

22.

Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK: Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002, 296 (5574): 1883-1886. 10.1126/science.1071420.CrossRefPubMed

23.

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. 2005, 65 (21): 9789-9798. 10.1158/0008-5472.CAN-05-0901.CrossRefPubMed

24.

He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K: Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002, 94 (11): 819-825.CrossRefPubMed

25.

Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, Tu GH, Koprivnikar K, VanRoey MJ, He Y, Alitalo K, Jooss K: Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 2005, 65 (15): 6901-6909. 10.1158/0008-5472.CAN-05-0408.CrossRefPubMed

26.

Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA: Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 2005, 97 (1): 14-21.CrossRefPubMed

27.

Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004, 5 (1): 74-80. 10.1038/ni1013.CrossRefPubMed

28.

Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M: Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol. 2001, 159 (3): 893-903.CrossRefPubMedPubMedCentral

29.

Pepper MS, Tille JC, Nisato R, Skobe M: Lymphangiogenesis and tumor metastasis. Cell Tissue Res. 2003, 314 (1): 167-177. 10.1007/s00441-003-0748-7.CrossRefPubMed

30.

Partanen TA, Alitalo K, Miettinen M: Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999, 86 (11): 2406-2412. 10.1002/(SICI)1097-0142(19991201)86:11<2406::AID-CNCR31>3.0.CO;2-E.CrossRefPubMed

31.

Kaushal V, Mukunyadzi P, Dennis RA, Siegel ER, Johnson DE, Kohli M: Stage-specific characterization of the vascular endothelial growth factor axis in prostate cancer: expression of lymphangiogenic markers is associated with advanced-stage disease. Clin Cancer Res. 2005, 11 (2 Pt 1): 584-593.PubMed

32.

Tuomela JM, Valta MP, Vaananen K, Harkonen PL: Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice. BMC Cancer. 2008, 8 (1): 81-10.1186/1471-2407-8-81.CrossRefPubMedPubMedCentral

33.

Valta MP, Tuomela J, Vuorikoski H, Loponen N, Väänänen RM, Pettersson K, Väänänen HK, Häärkönen PL: FGF-8b induces growth and rich vascularization in an orthotopic PC-3 model of prostate cancer. J Cell Biochem. 2009, 1;107 (4): 769-84. 10.1002/jcb.22175.CrossRef

34.

Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987, 162 (1): 156-159. 10.1016/0003-2697(87)90021-2.CrossRefPubMed

35.

He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K: 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. 2005, 65 (11): 4739-4746. 10.1158/0008-5472.CAN-04-4576.CrossRefPubMed

36.

Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K: Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 2001, 61 (5): 1786-1790.PubMed

37.

Janik P, Briand P, Hartmann NR: The effect of estrone-progesterone treatment on cell proliferation kinetics of hormone-dependent GR mouse mammary tumors. Cancer Res. 1975, 35 (12): 3698-3704.PubMed

38.

Jackson DG, Prevo R, Clasper S, Banerji S: LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol. 2001, 22 (6): 317-321. 10.1016/S1471-4906(01)01936-6.CrossRefPubMed

39.

Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K: Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA. 2002, 99 (13): 8868-8873. 10.1073/pnas.062040199.CrossRefPubMedPubMedCentral

40.

Stephenson RA, Dinney CP, Gohji K, Ordonez NG, Killion JJ, Fidler IJ: Metastatic model for human prostate cancer using orthotopic implantation in nude mice. J Natl Cancer Inst. 1992, 84 (12): 951-957. 10.1093/jnci/84.12.951.CrossRefPubMed

41.

Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K: Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002, 2 (8): 573-583. 10.1038/nrc863.CrossRefPubMed

42.

Stacker SA, Baldwin ME, Achen MG: The role of tumor lymphangiogenesis in metastatic spread. FASEB J. 2002, 16 (9): 922-934. 10.1096/fj.01-0945rev.CrossRefPubMed

43.

He Y, Karpanen T, Alitalo K: Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta. 2004, 1654 (1): 3-12.PubMed

44.

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. Blood. 2007, 109 (3): 1010-1017. 10.1182/blood-2006-05-021758.CrossRefPubMedPubMedCentral

45.

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. 2006, 66 (19): 9566-9575. 10.1158/0008-5472.CAN-06-1488.CrossRefPubMed

46.

Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK: Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res. 2004, 64 (13): 4400-4404. 10.1158/0008-5472.CAN-04-0752.CrossRefPubMed

47.

Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K: Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 2007, 67 (2): 593-599. 10.1158/0008-5472.CAN-06-3567.CrossRefPubMed

48.

Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K: Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008, 454 (7204): 656-660. 10.1038/nature07083.CrossRefPubMed

49.

Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, Senegas I, Laboudie P, Bonnin J, Cassan C, Savi P, ruggeri B, carmeliot P, Bono F, Herbert JM: Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun. 2004, 324 (2): 909-915. 10.1016/j.bbrc.2004.08.237.CrossRefPubMed

50.

Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK: Pathology: cancer cells compress intratumour vessels. Nature. 2004, 427 (6976): 695-10.1038/427695a.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/362/prepub

Title: Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors
Authors: Johanna Tuomela
Maija Valta
Jani Seppänen
Kati Tarkkonen
H Kalervo Väänänen
Pirkko Härkönen
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2009
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-9-362

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2009

Mammographic density and epithelial histopathologic markers

Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma - a case report

Case report: Malignant teratoma of the uterine corpus

Cripto-1 overexpression is involved in the tumorigenesis of nasopharyngeal carcinoma

Breast cancer epidemiology according to recognized breast cancer risk factors in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial Cohort

The -271 G>A polymorphism of kinase insert domain-containing receptor gene regulates its transcription level in patients with non-small cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer