| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Department of Pathology and Center of Excellence for Clinical and Experimental Oncology,* the Institute of Immunology, and the Department of Dermatology, University of Vienna-Allgemeines Krankenhaus, Vienna, Austria; and the Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Formation of lymphatic metastasis is the initial step of generalized spreading of tumor cells and predicts poor clinical prognosis. Lymphatic vessels generally arise within the peritumoral stroma, although the lymphangiopoietic vascular endothelial growth factors (VEGF)-C and -D are produced by tumor cells. In a carefully selected collection of human cervical cancers (stage pT1b1) we demonstrate by quantitative immunohistochemistry and in situ hybridization that density of lymphatic microvessels is significantly increased in peritumoral stroma, and that a subset of stromal cells express large amounts of VEGF-C and VEGF-D. The density of cells producing these vascular growth factors correlates with peritumoral inflammatory stroma reaction, lymphatic microvessel density, and indirectly with peritumoral carcinomatous lymphangiosis and frequency of lymph node metastasis. The VEGF-C- and VEGF-D-producing stroma cells were identified in situ as a subset of activated tumor-associated macrophages (TAMs) by expression of a panel of macrophage-specific markers, including CD68, CD23, and CD14. These TAMs also expressed the VEGF-C- and VEGF-D-specific tyrosine kinase receptor VEGFR-3. As TAMs are derived from monocytes in the circulation, a search in peripheral blood for candidate precursors of VEGFR-3-expressing TAMs revealed a subfraction of CD14-positive, VEGFR-3-expressing monocytes, that, however, failed to express VEGF-C and VEGF-D. Only after in vitro incubation with tumor necrosis factor-
, lipopolysaccharide, or VEGF-D did these monocytes start to synthesize VEGF-C de novo. In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer.
This article has been cited by other articles:
 |
|
 |
|
  T. P. Padera, A. H. Kuo, T. Hoshida, S. Liao, J. Lobo, K. R. Kozak, D. Fukumura, and R. K. Jain Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib Mol. Cancer Ther., August 1, 2008; 7(8): 2272 - 2279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sasaki, T. Nakamura, R. B. Rebhun, H. Cheng, K. S. Hale, R. Z. Tsan, I. J. Fidler, and R. R. Langley Modification of the Primary Tumor Microenvironment by Transforming Growth Factor {alpha}-Epidermal Growth Factor Receptor Signaling Promotes Metastasis in an Orthotopic Colon Cancer Model Am. J. Pathol., July 1, 2008; 173(1): 205 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sato VEGFR1 for Lymphangiogenesis: An Alternative Signaling Pathway? Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 604 - 605. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Thelen, A. Scholz, C. Benckert, W. Weichert, E. Dietz, B. Wiedenmann, P. Neuhaus, and S. Jonas Tumor-Associated Lymphangiogenesis Correlates with Lymph Node Metastases and Prognosis in Hilar Cholangiocarcinoma Ann. Surg. Oncol., March 1, 2008; 15(3): 791 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-H. Jeon, C. Jang, J. Han, R. P. Kataru, L. Piao, K. Jung, H. J. Cha, R. A. Schwendener, K. Y. Jang, K.-S. Kim, et al. Profound but Dysfunctional Lymphangiogenesis via Vascular Endothelial Growth Factor Ligands from CD11b+ Macrophages in Advanced Ovarian Cancer Cancer Res., February 15, 2008; 68(4): 1100 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Koyama, N. Kobayashi, M. Harada, M. Takeoka, Y. Kawai, K. Sano, M. Fujimori, J. Amano, T. Ohhashi, R. Kannagi, et al. Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis: Pivotal Role of a Hyaluronan-Rich Tumor Microenvironment Am. J. Pathol., January 1, 2008; 172(1): 179 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Brideau, M. J. Makinen, H. Elamaa, H. Tu, G. Nilsson, K. Alitalo, T. Pihlajaniemi, and R. Heljasvaara Endostatin Overexpression Inhibits Lymphangiogenesis and Lymph Node Metastasis in Mice Cancer Res., December 15, 2007; 67(24): 11528 - 11535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Iwata, M. R. Kano, A. Komuro, M. Oka, K. Kiyono, E. Johansson, Y. Morishita, M. Yashiro, K. Hirakawa, M. Kaminishi, et al. Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis Cancer Res., November 1, 2007; 67(21): 10181 - 10189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Sundar and T. S. Ganesan Role of Lymphangiogenesis in Cancer J. Clin. Oncol., September 20, 2007; 25(27): 4298 - 4307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Karagiannis, M. G. Bracher, J. Hunt, N. McCloskey, R. L. Beavil, A. J. Beavil, D. J. Fear, R. G. Thompson, N. East, F. Burke, et al. IgE-Antibody-Dependent Immunotherapy of Solid Tumors: Cytotoxic and Phagocytic Mechanisms of Eradication of Ovarian Cancer Cells J. Immunol., September 1, 2007; 179(5): 2832 - 2843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jackowski, M. Janusch, E. Fiedler, W. C. Marsch, E. J. Ulbrich, G. Gaisbauer, J. Dunst, D. Kerjaschki, and P. Helmbold Radiogenic Lymphangiogenesis in the Skin Am. J. Pathol., July 1, 2007; 171(1): 338 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cheng, D.-H. Huo, D.-M. Kuang, J. Yang, L. Zheng, and S.-M. Zhuang Human Macrophages Promote the Motility and Invasiveness of Osteopontin-Knockdown Tumor Cells Cancer Res., June 1, 2007; 67(11): 5141 - 5147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Donoghue, F. L. Lederman, B. J. Susil, and P. A.W. Rogers Lymphangiogensis of normal endometrium and endometrial adenocarcinoma Hum. Reprod., June 1, 2007; 22(6): 1705 - 1713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Goldman, J. M. Rutkowski, J. D. Shields, M. C. Pasquier, Y. Cui, H. G. Schmokel, S. Willey, D. J. Hicklin, B. Pytowski, and M. A. Swartz Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis FASEB J, April 1, 2007; 21(4): 1003 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Harrell, B. M. Iritani, and A. Ruddell Tumor-Induced Sentinel Lymph Node Lymphangiogenesis and Increased Lymph Flow Precede Melanoma Metastasis Am. J. Pathol., February 1, 2007; 170(2): 774 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Laakkonen, M. Waltari, T. Holopainen, T. Takahashi, B. Pytowski, P. Steiner, D. Hicklin, K. Persaud, J. R. Tonra, L. Witte, et al. Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth Cancer Res., January 15, 2007; 67(2): 593 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. E. Tobler and M. Detmar Tumor and lymph node lymphangiogenesis--impact on cancer metastasis J. Leukoc. Biol., October 1, 2006; 80(4): 691 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lamagna, M. Aurrand-Lions, and B. A. Imhof Dual role of macrophages in tumor growth and angiogenesis J. Leukoc. Biol., October 1, 2006; 80(4): 705 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Shayan, M. G. Achen, and S. A. Stacker Lymphatic vessels in cancer metastasis: bridging the gaps Carcinogenesis, September 1, 2006; 27(9): 1729 - 1738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Saaristo, T. Tammela, A. Farkkila, M. Karkkainen, E. Suominen, S. Yla-Herttuala, and K. Alitalo Vascular Endothelial Growth Factor-C Accelerates Diabetic Wound Healing Am. J. Pathol., September 1, 2006; 169(3): 1080 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Rutkowski, K. C. Boardman, and M. A. Swartz Characterization of lymphangiogenesis in a model of adult skin regeneration Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1402 - H1410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schmeisser, M. Christoph, A. Augstein, R. Marquetant, M. Kasper, R.C. Braun-Dullaeus, and R.H. Strasser Apoptosis of human macrophages by Flt-4 signaling: Implications for atherosclerotic plaque pathology Cardiovasc Res, September 1, 2006; 71(4): 774 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Massi, S Puig, A Franchi, J Malvehy, S Vidal-Sicart, M Gonzalez-Cao, G Baroni, S Ketabchi, J Palou, and M Santucci Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case-control study J. Clin. Pathol., February 1, 2006; 59(2): 166 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Miyata, S. Kanda, K. Ohba, K. Nomata, Y. Hayashida, J. Eguchi, T. Hayashi, and H. Kanetake Lymphangiogenesis and Angiogenesis in Bladder Cancer: Prognostic Implications and Regulation by Vascular Endothelial Growth Factors-A, -C, and -D Clin. Cancer Res., February 1, 2006; 12(3): 800 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Lewis and J. W. Pollard Distinct Role of Macrophages in Different Tumor Microenvironments Cancer Res., January 15, 2006; 66(2): 605 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gombos, X. Xu, C. S. Chu, P. J. Zhang, and G. Acs Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix Clin. Cancer Res., December 1, 2005; 11(23): 8364 - 8371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Wong, H. Haack, D. Crowley, M. Barry, R. T. Bronson, and R. O. Hynes Tumor-Secreted Vascular Endothelial Growth Factor-C Is Necessary for Prostate Cancer Lymphangiogenesis, but Lymphangiogenesis Is Unnecessary for Lymph Node Metastasis Cancer Res., November 1, 2005; 65(21): 9789 - 9798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kuroda, Y. Kitadai, S. Tanaka, X. Yang, N. Mukaida, M. Yoshihara, and K. Chayama Monocyte Chemoattractant Protein-1 Transfection Induces Angiogenesis and Tumorigenesis of Gastric Carcinoma in Nude Mice via Macrophage Recruitment Clin. Cancer Res., November 1, 2005; 11(21): 7629 - 7636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Bjorndahl, R. Cao, J. B. Burton, E. Brakenhielm, P. Religa, D. Galter, L. Wu, and Y. Cao Vascular Endothelial Growth Factor-A Promotes Peritumoral Lymphangiogenesis and Lymphatic Metastasis Cancer Res., October 15, 2005; 65(20): 9261 - 9268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Leibovici, H. B. Grossman, C. P. Dinney, R. E. Millikan, S. Lerner, Y. Wang, J. Gu, Q. Dong, and X. Wu Polymorphisms in Inflammation Genes and Bladder Cancer: From Initiation to Recurrence, Progression, and Survival J. Clin. Oncol., August 20, 2005; 23(24): 5746 - 5756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cursiefen, S. Ikeda, P. M. Nishina, R. S. Smith, A. Ikeda, D. Jackson, J.-S. Mo, L. Chen, M. R. Dana, B. Pytowski, et al. Spontaneous Corneal Hem- and Lymphangiogenesis in Mice with Destrin-Mutation Depend on VEGFR3 Signaling Am. J. Pathol., May 1, 2005; 166(5): 1367 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-R. Yang, S.-L. Hsieh, F.-M. Ho, and W.-W. Lin Decoy Receptor 3 Increases Monocyte Adhesion to Endothelial Cells via NF-{kappa}B-Dependent Up-Regulation of Intercellular Adhesion Molecule-1, VCAM-1, and IL-8 Expression J. Immunol., February 1, 2005; 174(3): 1647 - 1656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sipos, W. Klapper, M.-L. Kruse, H. Kalthoff, D. Kerjaschki, and G. Kloppel Expression of Lymphangiogenic Factors and Evidence of Intratumoral Lymphangiogenesis in Pancreatic Endocrine Tumors Am. J. Pathol., October 1, 2004; 165(4): 1187 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Chang, G. Garcia-Cardena, F. Farnebo, M. Fannon, E. J. Chen, C. Butterfield, M. A. Moses, R. C. Mulligan, J. Folkman, and A. Kaipainen Dose-dependent response of FGF-2 for lymphangiogenesis PNAS, August 10, 2004; 101(32): 11658 - 11663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Arenberg In Search of the Holy Grail: Lung Cancer Biomarkers Chest, August 1, 2004; 126(2): 325 - 326. [Full Text] [PDF]
|
|
|
|
|
|
I Esposito, M Menicagli, N Funel, F Bergmann, U Boggi, F Mosca, G Bevilacqua, and D Campani Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma J. Clin. Pathol., June 1, 2004; 57(6): 630 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kerjaschki, H. M. Regele, I. Moosberger, K. Nagy-Bojarski, B. Watschinger, A. Soleiman, P. Birner, S. Krieger, A. Hovorka, G. Silberhumer, et al. Lymphatic Neoangiogenesis in Human Kidney Transplants Is Associated with Immunologically Active Lymphocytic Infiltrates J. Am. Soc. Nephrol., March 1, 2004; 15(3): 603 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yamanaka, T. Morisaki, H. Nakashima, A. Tasaki, M. Kubo, H. Kuga, C. Nakahara, K. Nakamura, H. Noshiro, T. Yao, et al. Interleukin 1{beta} Enhances Invasive Ability of Gastric Carcinoma through Nuclear Factor-{kappa}B Activation Clin. Cancer Res., March 1, 2004; 10(5): 1853 - 1859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Su, J.-Y. Shih, M.-L. Yen, Y.-M. Jeng, C.-C. Chang, C.-Y. Hsieh, L.-H. Wei, P.-C. Yang, and M.-L. Kuo Cyclooxygenase-2 Induces EP1- and HER-2/Neu-Dependent Vascular Endothelial Growth Factor-C Up-Regulation: A Novel Mechanism of Lymphangiogenesis in Lung Adenocarcinoma Cancer Res., January 15, 2004; 64(2): 554 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S A Hoption Cann, J P van Netten, and C van Netten Dr William Coley and tumour regression: a place in history or in the future Postgrad. Med. J., December 1, 2003; 79(938): 672 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Monti, B. E. Leone, F. Marchesi, G. Balzano, A. Zerbi, F. Scaltrini, C. Pasquali, G. Calori, F. Pessi, C. Sperti, et al. The CC Chemokine MCP-1/CCL2 in Pancreatic Cancer Progression: Regulation of Expression and Potential Mechanisms of Antimalignant Activity Cancer Res., November 1, 2003; 63(21): 7451 - 7461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matsui, K. Nagy-Bojarsky, P. Laakkonen, S. Krieger, K. Mechtler, S. Uchida, S. Geleff, D.-H. Kang, R. J. Johnson, and D. Kerjaschki Lymphatic Microvessels in the Rat Remnant Kidney Model of Renal Fibrosis: Aminopeptidase P and Podoplanin Are Discriminatory Markers for Endothelial Cells of Blood and Lymphatic Vessels J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1981 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hamrah, L. Chen, Q. Zhang, and M. R. Dana Novel Expression of Vascular Endothelial Growth Factor Receptor (VEGFR)-3 and VEGF-C on Corneal Dendritic Cells Am. J. Pathol., July 1, 2003; 163(1): 57 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-M. Maula, M. Luukkaa, R. Grenman, D. Jackson, S. Jalkanen, and R. Ristamaki Intratumoral Lymphatics Are Essential for the Metastatic Spread and Prognosis in Squamous Cell Carcinomas of the Head and Neck Region Cancer Res., April 15, 2003; 63(8): 1920 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
