Expression of Vascular Endothelial Growth Factors C and D Correlates with Lymphangiogenesis and Lymph Node Metastasis in Lung Adenocarcinoma

Abstract

Background: Vascular endothelial growth factors (VEGF)-C and -D have been reported to be lymph-specific growth factors. In this study we analyzed the intra- and peritumoral microlymphatic vessel density (MLVD) and the expression of VEGF‐C and -D in lung adenocarcinoma. Methods: Tissue samples were obtained from 48 patients who underwent surgery for lung adenocarcinoma. The expression of VEGF‐C, -D and MLVD was examined by immunohistochemistry, and the correlation with lymph node metastasis and clinicopathological features was evaluated. Results: Immunohistochemical analysis revealed the presence of VEGF‐C and -D immunoreactivity in 70.8 % (34/48) and 58.3 % (28/48) of the tissue samples, respectively. The group with a high expression of VEGF‐C and -D in the tumor margins had a higher incidence of lymph node metastasis. MLVD in both the VEGF‐C and the VEGF‐D positive groups was higher than that in the negative groups, and the lymph node metastasis was likewise higher. Conclusion: VEGF‐C and -D may play important roles in lymphangiogenesis and lymph node metastasis in lung adenocarcinoma.

Key words

vascular endothelial growth factor - lymphangiogenesis - lung adenocarcinoma

References

• 1 Stacker S A, Caesar C, Baldwin M E et al. VEGF‐D promotes the metastasis spread of tumor cells via the lymphatics.  Nat Med. 2001;  7 186-191
• 2 He Y, Kozaki K, Karpanen T et al. Suppression of tumor lymphangiogenesis and lymph nodemetastasis by blocking vascular endothelial growth factor receptor 3 signaling.  J Natl Cancer Inst. 2002;  94 819-825
• 3 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 USA. 1995;  92 3566-3570
• 4 Ishikawa M, Kitayama J, Kazama S et al. Expression of vascular endothelial growth factor (VEGF)-C in preoperative biopsy specimens and metastatic foci of regional lymph nodes in submucosal gastric carcinoma [J].  World J Surg Oncol. 2005;  3 2
• 5 Salven P, Lymboussaki A, Heikkila P et al. Vascular endothelial growth factors VEGF‐B and VEGF‐C are expressed in human tumors.  Am J Pathol. 1998;  153 103-108
• 6 Bunone G, Vigneri P, Mariani L et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features.  Am J Pathol. 1999;  155 1967-1976
• 7 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 Cancer. 1999;  80 309-313
• 8 Krishnan J, Kirkin V, Steffen A, Hegen M, Weih D, Tomarev S et al. 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. 2003;  63 713-722
• 9 Veikkola T, Jussila L, Makinen T et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice.  EMBO J. 2001;  20 1223-1231
• 10 Shimizu K, Kubo H, Yamaguchi K et al. Suppression of VEGFR‐3 signaling inhibits lymph node metastasis in gastric cancer.  Cancer Sci. 2004;  95 328-333
• 11 Onogawa S, Kitadai Y, Tanaka S, Kuwai T, Kimura S, Chayama K. Expression of VEGF‐C and VEGF‐D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma.  Cancer Sci. 2004;  95 32-39
• 12 Nakamura Y, Yasuoka H, Tsujimoto M et al. Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer.  Clin Cancer Res. 2003;  9 5313-5317
• 13 Yokoyama Y, Charnock-Jones D S, Licence D et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma.  Br J Cancer. 2003;  88 237-244
• 14 Nathanson S D. Insights into the mechanisms of lymph node metastasis.  Cancer. 2003;  98 413-423
• 15 O-Charoenrat P, Rhys-Evans P, Eccles S A. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis.  Cancer (Phila). 2001;  92 556-568
• 16 Maula S M, Luukkaa M, Grenman R, Jackson D, Jalkanen S, Ristamaki R. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region.  Cancer Res. 2003;  63 1920-1926
• 17 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. 1999;  154 385-394
• 18 Carreira C M, Nasser S M, Di Tomaso E et al. LYVE‐1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis.  Cancer Res. 2001;  61 8079-8084
• 19 Trojan L, Michel M S, Rensch F, Jackson D G, 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. 2004;  172 103-107
• 20 Mandriota S J, Jussila L, Jeltsch M et al. Vasucular endothelial growth factor-C-mediated lymphangiogenesis promotes tumor metastasis.  EMBO J. 2001;  20 672-682