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Molecular/Cancer Biology Laboratory, Haartman Institute and Ludwig Institute for Cancer Research, FIN-00014 University of Helsinki, Finland [T. K., M. J. K., H. K., K. A.]; Apoptosis Laboratory, Danish Cancer Society, DK-2100 Copenhagen, Denmark [M. E., M. J.]; and A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland [S. Y-H.]
| ABSTRACT |
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| Introduction |
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| Materials and Methods |
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chain and VEGFR-1-Ig, containing the first five immunoglobulin homology domains of VEGFR-1 in a similar construct (18)
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Production and Analysis of Transfected Cells.
The MCF-7S1 subclone of the human MCF-7 breast carcinoma cell line was transfected with plasmid DNA by electroporation, and stable cell pools were selected and cultured as described previously (19)
. The cells were metabolically labeled in methionine and cysteine free MEM (Life Technologies, Inc.) supplemented with 100 µCi/ml [35S]methionine and [35S]cysteine (Redivue Pro-Mix; Amersham Pharmacia Biotech). The labeled growth factors were immunoprecipitated from the conditioned medium using antibodies against VEGF-C (1)
or VEGF (MAB293; R & D Systems). The immunocomplexes and the VEGFR-Ig fusion proteins were precipitated using protein A-Sepharose (Amersham Pharmacia Biotech), washed twice in 0.5% BSA, 0.02% Tween 20 in PBS, and once in PBS and analyzed in SDS-PAGE under reducing conditions.
Cell Proliferation and Tumorigenesis Assays.
Cells (20,000/well) were plated in quadruplicate in 24-well plates, trypsinized on replicate plates after 1, 4, 6, or 8 days, and counted using a hemocytometer. Fresh medium was provided after 4 and 6 days. For the tumorigenesis assay, subconfluent cultures were harvested by trypsinization and washed twice, and 107 cells in PBS were inoculated into the fat pads of the second (axillar) mammary gland of ovarectomized SCID mice, carrying s.c. 60-day slow-release pellets containing 0.72 mg of 17ß-estradiol (Innovative Research of America). The ovarectomy and implantation of the pellets were done 48 days before tumor cell inoculation. Tumor length and width were measured twice weekly in a blinded manner, and the tumor volume was calculated as the
, assuming that the tumor is a hemi-ellipsoid and the depth is the same as the width (20)
.
Histology and Quantitation of the Blood Vessels.
The tumors were excised, fixed in 4% paraformaldehyde (pH 7.0) for 24 h, and embedded in paraffin. Sections (7 µm) were immunostained with monoclonal antibodies against PECAM-1 (PharMingen), VEGFR-3 (21)
, PCNA (Zymed Laboratories), or polyclonal antibodies against LYVE-1 (a kind gift from Dr. David G. Jackson, University of Oxford, Oxford, United Kingdom; Ref. 22
), VEGF-C (1)
or laminin (a kind gift from Dr. Karl Tryggvason, Karolinska Institute, Stockholm, Sweden) according to published protocols (14)
. The average of the number of the PECAM-1-positive vessels was determined from three areas (x60) of the highest vascular density (vascular hot spots) in a section. All histological analysis was done using blinded tumor samples.
Adenoviral Expression of Soluble VEGFR-3 and Evans Blue Draining Assay.
The cDNA coding for the VEGFR-3-Ig fusion protein was subcloned into the pAdCMV plasmid, constructed by subcloning the human cytomegalovirus immediate-early promoter, the multiple cloning site, and the bovine growth hormone gene polyadenylation signal from the pcDNA3 (Invitrogen) into the pAdBglII vector, and the adenoviruses were produced as described previously (23)
. The VEGFR-3-Ig or LacZ control (23)
adenoviruses, 109 pfu/mouse, were injected i.v. into the SCID mice 3 h before the tumor cell inoculation. After 3 weeks, four mice from each group were narcotized, the ventral skin was opened, and 510 µl of 3% Evans blue dye (Sigma) in PBS were injected into the tumor. The drainage of the dye from the tumor was followed macroscopically.
| Results |
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2-fold (Fig. 3)
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VEGF-C-induced Lymphangiogenesis Is Inhibited by a Circulating Soluble VEGFR-3 Fusion Protein.
In human breast cancer, the sentinel node method is used to trace lymphatic drainage and metastatic spread (reviewed in Ref. 24
). To trace lymphatic drainage of the MCF-7 tumors, Evans blue dye was injected into VEGF-C-overexpressing or control tumors in mice infected with VEGFR-3-Ig or control adenovirus. Control experiments indicated that infection of cultured human embryonic kidney cells with the VEGFR-3-Ig adenovirus resulted in the secretion of high amounts of the soluble VEGFR-3-Ig fusion protein, and i.v. infection of mice led to high systemic levels of the VEGFR-3-Ig fusion protein in the serum.5
Injection of Evans blue dye into the tumors resulted in the staining of lymphatic but not blood vessels and revealed an increased number of enlarged lymphatic vessels surrounding the VEGF-C-overexpressing tumors (Fig. 4G)
when compared with control tumors (Fig. 4H)
. Most of the enlarged lymphatic vessels were absent from VEGF-C-overexpressing tumors in mice treated with the VEGFR-3-Ig adenovirus (Fig. 4I)
. These results were confirmed by immunohistochemical analysis of the tumor samples (data not shown).
| Discussion |
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Because of the lack of specific markers, it has been questioned whether tumors can actively induce lymphangiogenesis or if solid tumors just encompass by overgrowth the already existing lymphatic vessels and compress them because of the high interstitial fluid pressure inside the tumor. In various experimental models, the latter seems to be the case (25 , 26) . Here, for the first time, we show that overexpression of VEGF-C can induce the growth of lymphatic vessels in association with experimental tumors. The VEGF-C-induced lymphatic vessels in the tumor periphery were highly hyperplastic and mostly filled with tumor cells, whereas the lymphatic vessels inside the tumor were flattened and in general without a lumen. These intratumoral lymphatic vessels may be trapped by multiple expanding tumor cell islets in tumor xenografts, but they may be rare in naturally occurring tumors. Unlike lymphatic endothelial cells in normal adult tissues, the lymphatic endothelial cells associated with the MCF-7 tumors were actively proliferating. On the basis of this information, we speculated that most of the peri- and intratumoral lymphatic vessels were generated by proliferation of the endothelial cells of preexisting lymphatic vessels.
Although the spread of cancer through the lymphatics into the regional lymph nodes has long been an important prognostic indicator in clinical use, tumor metastasis at the mechanistic level is still poorly understood. The growth of tumor cells inside the enlarged lymphatic vessels associated with the VEGF-C-overexpressing tumors in this study resembles the peritumoral lymphatic invasion, which correlates with metastatic spread to the lymph nodes and poor survival in human breast cancer (27) . This suggests that expression of VEGF-C can promote tumor metastasis via the lymphatic system. Despite this, we did not detect macroscopic metastases in the lymph nodes of mice bearing the VEGF-C-overexpressing tumors (data not shown). This may be attributable to the facts that MCF-7 tumors rarely form macrometastasis (28) and that the duration of our experiments was relatively short. However, lymph node micrometastases were promoted by VEGF-C overexpression in the MCF-7 tumors.6
VEGF and its receptor VEGFR-2 are considered to be the main regulators of tumor angiogenesis (2 , 3) . Also VEGFR-3, although normally restricted to the lymphatic endothelial cells in adults, is up-regulated in the blood vessels of many kinds of solid tumors (9 , 14) . A previous report suggested that VEGFR-3 could be involved in the maintenance of the integrity of the endothelial cell lining during tumor angiogenesis (21) . Therefore, we speculated that VEGF-C may influence tumor neovascularization. However, in the present tumor model, overexpression of VEGF-C, in comparison with VEGF, did not significantly increase tumor angiogenesis. Instead, its effects were mainly lymphangiogenic.
The increased growth of the primary tumors overexpressing VEGF-C was unexpected, given that VEGF-C had no effect on tumor cell proliferation in cell culture or on tumor angiogenesis. The effect of VEGF-C on tumor growth was not simply attributable to variation between the cell pools, as shown by the ability of the VEGFR-3 fusion protein to inhibit the growth of VEGF-C-overexpressing tumors. By injecting Evans blue dye into the tumors, we observed that an increased number of large draining lymphatic vessels were associated with the VEGF-C-overexpressing tumors. One could speculate that the higher number of functional lymphatic vessels may result in a better lymphatic drainage and thus a lower interstitial pressure and enhanced blood perfusion of the VEGF-C-overexpressing tumors.
In conclusion, our results show that VEGF-C produced by tumor cells can induce the growth of lymphatic vessels around tumors and thus facilitate the intralymphatic spread of cancer. Because of the specific lymphangiogenic response and the lack of significant effects on tumor angiogenesis, the VEGF-C-overexpressing MCF-7 breast carcinoma represents a useful model to study the development of tumor-associated lymphatic vessels. Furthermore, the data suggest that inhibition of tumor-associated lymphangiogenesis, for example by gene therapy using soluble VEGFR-3 proteins, could be a valuable way of inhibiting tumor metastasis.
| ACKNOWLEDGMENTS |
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Note Added in Proof
While this paper was being processed, three other papers have also reported increased tumor lymphangiogenesis in different VEGF-C or VEGF-D overexpressing tumor models (Stacker et al.Nature Medicine, 7:186191, Skobe et al.Nature Med., 7:192198, Mandriotta et al.EMBO J, in press). In these models, also lymphatic metastasis was enhanced. Furthermore, Kadambi et al.(Cancer Res., in press, 2001) report that in the early stages of tumorigenesis, VEGF-C can increase tumor angiogenesis as well.
| FOOTNOTES |
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1 Supported by the Finnish Academy, the Sigrid Juselius Foundation, the University of Helsinki Hospital, the State Technology Development Center, the European Union, the Finnish Cancer Organization, Finnish Cultural Foundation, Ida Montini Foundation, Emil Aaltonen Foundation, Research and Science Foundation of Farmos, the Danish Cancer Society, the Danish Medical Research Council, and the Jens Aage and Edith Ingeborg Sørensen Memorial Foundation. ![]()
2 These authors contributed equally to this work. ![]()
3 To whom requests for reprints should be addressed, at Molecular/Cancer Biology Laboratory, Haartman Institute, P. O. Box 21 (Haarmaninkatu 3), FIN-00014 University of Helsinki, Finland. Phone: 358-9-191-26434; Fax: 358-9-191-26448; E-mail: Kari.Alitalo{at}Helsinki.fi ![]()
4 The abbreviations used are: VEGF-C, vascular endothelial growth factor C; VEGFR, VEGF receptor; SCID, severe combined immunodeficient; PCNA, proliferating cell nuclear antigen; Ig, immunoglobulin. ![]()
5 T. Karpanen and T. Makinen, unpublished data. ![]()
6 M. Mattila, J. Ruohola, and C. P. Härkönen, unpublished data. ![]()
Received 12/29/00. Accepted 1/18/01.
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Y. Zeng, K. Opeskin, M. E. Baldwin, L. G. Horvath, M. G. Achen, S. A. Stacker, R. L. Sutherland, and E. D. Williams Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer Clin. Cancer Res., August 1, 2004; 10(15): 5137 - 5144. [Abstract] [Full Text] [PDF] |
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N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain Peritumor Lymphatics Induced by Vascular Endothelial Growth Factor-C Exhibit Abnormal Function Cancer Res., July 1, 2004; 64(13): 4400 - 4404. [Abstract] [Full Text] [PDF] |
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M M Vleugel, R Bos, P van der Groep, A E Greijer, A Shvarts, H V Stel, E van der Wall, and P J van Diest Lack of lymphangiogenesis during breast carcinogenesis J. Clin. Pathol., July 1, 2004; 57(7): 746 - 751. [Abstract] [Full Text] [PDF] |
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P. Laakkonen, M. E. Akerman, H. Biliran, M. Yang, F. Ferrer, T. Karpanen, R. M. Hoffman, and E. Ruoslahti Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells PNAS, June 22, 2004; 101(25): 9381 - 9386. [Abstract] [Full Text] [PDF] |
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Y. He, I. Rajantie, M. Ilmonen, T. Makinen, M. J. Karkkainen, P. Haiko, P. Salven, and K. Alitalo Preexisting Lymphatic Endothelium but not Endothelial Progenitor Cells Are Essential for Tumor Lymphangiogenesis and Lymphatic Metastasis Cancer Res., June 1, 2004; 64(11): 3737 - 3740. [Abstract] [Full Text] [PDF] |
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K. Persaud, J.-C. Tille, M. Liu, Z. Zhu, X. Jimenez, D. S. Pereira, H.-Q. Miao, L. A. Brennan, L. Witte, M. S. Pepper, et al. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C J. Cell Sci., June 1, 2004; 117(13): 2745 - 2756. [Abstract] [Full Text] [PDF] |
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Y. Nakamura, H. Yasuoka, M. Tsujimoto, Q. Yang, S. Imabun, M. Nakahara, K. Nakao, M. Nakamura, I. Mori, and K. Kakudo Flt-4-Positive Vessel Density Correlates with Vascular Endothelial Growth Factor-D Expression, Nodal Status, and Prognosis in Breast Cancer Clin. Cancer Res., November 1, 2003; 9(14): 5313 - 5317. [Abstract] [Full Text] [PDF] |
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J. Dixelius, T. Makinen, M. Wirzenius, M. J. Karkkainen, C. Wernstedt, K. Alitalo, and L. Claesson-Welsh Ligand-induced Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) Heterodimerization with VEGFR-2 in Primary Lymphatic Endothelial Cells Regulates Tyrosine Phosphorylation Sites J. Biol. Chem., October 17, 2003; 278(42): 40973 - 40979. [Abstract] [Full Text] [PDF] |
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S. S. Dadras, T. Paul, J. Bertoncini, L. F. Brown, A. Muzikansky, D. G. Jackson, U. Ellwanger, C. Garbe, M. C. Mihm, and M. Detmar Tumor Lymphangiogenesis: A Novel Prognostic Indicator for Cutaneous Melanoma Metastasis and Survival Am. J. Pathol., June 1, 2003; 162(6): 1951 - 1960. [Abstract] [Full Text] [PDF] |
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E. D. Emberley, Y. Niu, E. Leygue, L. Tomes, R. D. Gietz, L. C. Murphy, and P. H. Watson Psoriasin Interacts with Jab1 and Influences Breast Cancer Progression Cancer Res., April 15, 2003; 63(8): 1954 - 1961. [Abstract] [Full Text] [PDF] |
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Y. Tang, D. Zhang, L. Fallavollita, and P. Brodt Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis Are Regulated by the Type I Insulin-like Growth Factor Receptor Cancer Res., March 15, 2003; 63(6): 1166 - 1171. [Abstract] [Full Text] [PDF] |
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L. Yuan, D. Moyon, L. Pardanaud, C. Breant, M. J. Karkkainen, K. Alitalo, and A. Eichmann Abnormal lymphatic vessel development in neuropilin 2 mutant mice Development, March 12, 2003; 129(20): 4797 - 4806. [Abstract] [Full Text] [PDF] |
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P.-W. Tsai, S.-G. Shiah, M.-T. Lin, C.-W. Wu, and M.-L. Kuo Up-regulation of Vascular Endothelial Growth Factor C in Breast Cancer Cells by Heregulin-beta 1. A CRITICAL ROLE OF p38/NUCLEAR FACTOR-kappa B SIGNALING PATHWAY J. Biol. Chem., February 14, 2003; 278(8): 5750 - 5759. [Abstract] [Full Text] [PDF] |
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J. Krishnan, V. Kirkin, A. Steffen, M. Hegen, D. Weih, S. Tomarev, J. Wilting, and J. P. Sleeman Differential in Vivo and in Vitro Expression of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in Tumors and Its Relationship to Lymphatic Metastasis in Immunocompetent Rats Cancer Res., February 1, 2003; 63(3): 713 - 722. [Abstract] [Full Text] [PDF] |
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S. Hirakawa, Y.-K. Hong, N. Harvey, V. Schacht, K. Matsuda, T. Libermann, and M. Detmar Identification of Vascular Lineage-Specific Genes by Transcriptional Profiling of Isolated Blood Vascular and Lymphatic Endothelial Cells Am. J. Pathol., February 1, 2003; 162(2): 575 - 586. [Abstract] [Full Text] [PDF] |
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O. Straume, D. G. Jackson, and L. A. Akslen Independent Prognostic Impact of Lymphatic Vessel Density and Presence of Low-Grade Lymphangiogenesis in Cutaneous Melanoma Clin. Cancer Res., January 1, 2003; 9(1): 250 - 256. [Abstract] [Full Text] [PDF] |
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P. Salven, S. Mustjoki, R. Alitalo, K. Alitalo, and S. Rafii VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells Blood, January 1, 2003; 101(1): 168 - 172. [Abstract] [Full Text] [PDF] |
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R. Clarijs, L. Schalkwijk, U. B. Hofmann, D. J. Ruiter, and R. M. W. de Waal Induction of Vascular Endothelial Growth Factor Receptor-3 Expression on Tumor Microvasculature as a New Progression Marker in Human Cutaneous Melanoma Cancer Res., December 1, 2002; 62(23): 7059 - 7065. [Abstract] [Full Text] [PDF] |
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H. Dafni, T. Israely, Z. M. Bhujwalla, L. E. Benjamin, and M. Neeman Overexpression of Vascular Endothelial Growth Factor 165 Drives Peritumor Interstitial Convection and Induces Lymphatic Drain: Magnetic Resonance Imaging, Confocal Microscopy, and Histological Tracking of Triple-labeled Albumin Cancer Res., November 15, 2002; 62(22): 6731 - 6739. [Abstract] [Full Text] [PDF] |
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M. Detmar and S. Hirakawa The Formation of Lymphatic Vessels and Its Importance in the Setting of Malignancy J. Exp. Med., September 16, 2002; 196(6): 713 - 718. [Full Text] [PDF] |
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A. Saaristo, T. Veikkola, T. Tammela, B. Enholm, M. J. Karkkainen, K. Pajusola, H. Bueler, S. Yla-Herttuala, and K. Alitalo Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects J. Exp. Med., September 16, 2002; 196(6): 719 - 730. [Abstract] [Full Text] [PDF] |
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S. F. Schoppmann, P. Birner, J. Stockl, R. Kalt, R. Ullrich, C. Caucig, E. Kriehuber, K. Nagy, K. Alitalo, and D. Kerjaschki Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis Am. J. Pathol., September 1, 2002; 161(3): 947 - 956. [Abstract] [Full Text] [PDF] |
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S. A. STACKER, M. E. BALDWIN, and M. G. ACHEN The role of tumor lymphangiogenesis in metastatic spread FASEB J, July 1, 2002; 16(9): 922 - 934. [Abstract] [Full Text] [PDF] |
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L. Jussila and K. Alitalo Vascular Growth Factors and Lymphangiogenesis Physiol Rev, July 1, 2002; 82(3): 673 - 700. [Abstract] [Full Text] [PDF] |
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H. Kubo, R. Cao, E. Brakenhielm, T. Makinen, Y. Cao, and K. Alitalo Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea PNAS, June 25, 2002; 99(13): 8868 - 8873. [Abstract] [Full Text] [PDF] |
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T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, et al. Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics Science, June 7, 2002; 296(5574): 1883 - 1886. [Abstract] [Full Text] [PDF] |
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Y. He, K.-i. Kozaki, T. Karpanen, K. Koshikawa, S. Yla-Herttuala, T. Takahashi, and K. Alitalo Suppression of Tumor Lymphangiogenesis and Lymph Node Metastasis by Blocking Vascular Endothelial Growth Factor Receptor 3 Signaling J Natl Cancer Inst, June 5, 2002; 94(11): 819 - 825. [Abstract] [Full Text] [PDF] |
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G. Oliver and M. Detmar The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature Genes & Dev., April 1, 2002; 16(7): 773 - 783. [Full Text] [PDF] |
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R. K. Jain and B. T. Fenton Intratumoral Lymphatic Vessels: A Case of Mistaken Identity or Malfunction? J Natl Cancer Inst, March 20, 2002; 94(6): 417 - 421. [Full Text] [PDF] |
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O. Straume and L. A. Akslen Importance of Vascular Phenotype by Basic Fibroblast Growth Factor, and Influence of the Angiogenic Factors Basic Fibroblast Growth Factor/Fibroblast Growth Factor Receptor-1 and Ephrin-A1/EphA2 on Melanoma Progression Am. J. Pathol., March 1, 2002; 160(3): 1009 - 1019. [Abstract] [Full Text] [PDF] |
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T. MAKINEN and K. ALITALO Molecular Mechanisms of Lymphangiogenesis Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 189 - 196. [Abstract] [PDF] |
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T. Matsumoto and L. Claesson-Welsh VEGF Receptor Signal Transduction Sci. Signal., December 11, 2001; 2001(112): re21 - re21. [Abstract] [Full Text] [PDF] |
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J. F. Wang, X.-F. Zhang, and J. E. Groopman Stimulation of beta 1 Integrin Induces Tyrosine Phosphorylation of Vascular Endothelial Growth Factor Receptor-3 and Modulates Cell Migration J. Biol. Chem., November 2, 2001; 276(45): 41950 - 41957. [Abstract] [Full Text] [PDF] |
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T. Karpanen and K. Alitalo Lymphatic Vessels as Targets of Tumor Therapy? J. Exp. Med., September 17, 2001; 194(6): F37 - F42. [Full Text] [PDF] |
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M. Skobe, L. M. Hamberg, T. Hawighorst, M. Schirner, G. L. Wolf, K. Alitalo, and M. Detmar Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma Am. J. Pathol., September 1, 2001; 159(3): 893 - 903. [Abstract] [Full Text] [PDF] |
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