Abstract
The presence of lymph node metastasis is predictive of poor prognosis in solid tumors. Demonstration of specific markers of lymphatic endothelial cells has facilitated the study of the molecular mechanisms of metastasis, particularly lymphangiogenesis. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 axis has been the most extensively studied, but other molecular pathways are also involved, such as fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, VEGF-A, hepatocyte growth factor (HGF), insulin-like growth factor (IGF)-1 and -1R, and cyclooxygenase-2. Several strategies are currently being developed to prevent lymphatic metastasis, mainly targeting the VEGF-C/VEGF-D/VEGFR-3 axis: inhibiting maturation and activation of VEGF-C and VEGF-D by successive proteolyses, inhibiting binding of ligands to their receptor, and using tyrosine kinase inhibitors. Many questions remain and will be discussed in this article, particularly the role of lymph node metastasis in the development of visceral metastases, possible toxicities of antilymphangiogenic treatments, and their possible interactions with intratumoral penetration of other anticancer agents.
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References
Fisher B, Fisher ER (1966) The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg Gynecol Obstet 122:791–798
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410
Jain RK, Duda DG, Clark JW, Loeffler JS (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24–40
Hayes DF (2005) Prognostic and predictive factors revisited. Breast 14:493–499
Pepper MS (2001) Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7:462–468
Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K (2002) Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2:573–583
Swartz MA, Skobe M (2001) Lymphatic function, lymphangiogenesis, and cancer metastasis. Microsc Res Tech 55:92–99
Jussila L, Alitalo K (2002) Vascular growth factors and lymphangiogenesis. Physiol Rev 82:673–700
Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438:946–953
Pepper MS (2000) Lymphangiogenesis and tumor metastasis: more questions than answers. Lymphology 33:144–147
Sleeman JP, Krishnan J, Kirkin V, Baumann P (2001) Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech 55:61–69
Maula SM, Luukkaa M, Grenman R, Jackson D, Jalkanen S, Ristamaki R (2003) Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 63:1920–1926
Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960
Hall FT, Freeman JL, Asa SL, Jackson DG, Beasley NJ (2003) Intratumoral lymphatics and lymph node metastases in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 129:716–719
Kyzas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D (2005) Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J Pathol 206:170–177
Thiele W, Sleeman JP (2006) Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol 124:224–241
Achen MG, Stacker SA (2006) Tumor lymphangiogenesis and metastatic spread-New players begin to emerge. Int J Cancer 119(8):1755–1760
Taipale J, Makinen T, Arighi E, Kukk E, Karkkainen M, Alitalo K (1999) Vascular endothelial growth factor-3. Curr Top Microbiol Immunol 237:85–96
Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (1997) Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16:3898–3911
Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) 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 USA 95:548–553
Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K (2001) Signaling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223–1231
Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96–109
Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205
Bradley K, Loughran SJ, Davydova N, Stacker SA, Achen MG (2005) Mechanisms of lymphangiogenesis: targets for blocking the metastatic spread of cancer. Curr Cancer Drug Targets 5:561–571
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198
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 (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682
Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191
Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790
Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M (2001) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903
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 (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886
Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y (2003) Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non-small cell lung carcinoma. Cancer 97:457–464
Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H, Tanaka F (2004) Clinical significance of VEGF-C status in tumor cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer 91:498–503
Kojima H, Shijubo N, Yamada G, Ichimiya S, Abe S, Satoh M, Sato N (2005) Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 104:1668–1677
Li Q, Dong X, Gu W, Qiu X, Wang E (2003) Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (Engl.) 116:727–730
Saintigny P, Kambouchner M, Gomes N, Sainte-Catherine O, Vassy R, Breau JL, Morère JF, Bernaudin JF, Kraemer M (2006) VEGFR-3 and VEGF-C coexpression in non-small-cell lung carcinomatous cells is associated with cell proliferation and lymph node metastasis. (submitted for publication)
Achen MG, Williams RA, Baldwin ME, Lai P, Roufail S, Alitalo K, Stacker SA (2002) The angiogenic and lymphangiogenic factor vascular endothelial growth factor-D exhibits a paracrine mode of action in cancer. Growth Factors 20:99–107
Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K (2002) Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 99:8868–8873
Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101:11658–11663
Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6:333–345
Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423
Lohela M, Morisada T, Tornberg J, Norrmen C, Oike Y, Pajusola K, Thurston G, Suda T, Yla-Herttuala S, Alitalo K (2005) Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105:4642–4648
Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506
Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050
Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18:1111–1113
Bjorndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y (2005) Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 65:9261–9268
Ishigami SI, Arii S, Furutani M, Niwano M, Harada T, Mizumoto M, Mori A, Onodera H, Imamura M (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78:1379–1384
Shih CH, Ozawa S, Ando N, Ueda M, Kitajima M (2000) Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res 6:1161–1168
O-charoenrat P, Rhys-Evans P, Eccles SA (2001) Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 92:556–568
Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24(16):2885–2895
Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 102:15593–15598
Tang Y, Zhang D, Fallavollita L, Brodt P (2003) Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res 63:1166–1171
Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM (2004) Cyclooxygenases in cancer: progress and perspective. Cancer Lett 215:1–20
Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (2004) 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 64:554–564
Timoshenko AV, Chakraborty C, Wagner GF, Lala PK (2006) COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer 94:1154–1163
Zhang J, Ji J, Yuan F, Zhu L, Yan C, Yu YY, Liu BY, Zhu ZG, Lin YZ (2005) Cyclooxygenase-2 expression is associated with VEGF-C and lymph node metastases in gastric cancer patients. Biomed Pharmacother 59(Suppl 2):S285–S288
Soumaoro LT, Uetake H, Takagi Y, Iida S, Higuchi T, Yasuno M, Enomoto M, Sugihara K (2006) Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis. Dis Colon Rectum 49:392–398
von Rahden BH, Stein HJ, Puhringer F, Koch I, Langer R, Piontek G, Siewert JR, Hofler H, Sarbia M (2005) Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res 65:5038–5044
Kyzas PA, Stefanou D, Agnantis NJ (2005) COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma. Mod Path 18:153–160
Alitalo K, Mohla S, Ruoslahti E (2004) Lymphangiogenesis and cancer: meeting report. Cancer Res 64:9225–9229
Balkwill F (2004) Cancer and the chemokines network. Nat Rev Cancer 4:540–550
Muller A, Homey B, Soto H et al (2001) Involvement of chemokines receptors in breast cancer metastasis. Nature 410:50–56
Wiley HE, Gonzalez EB, Maki S et al (2001) Expression of CC chemokines receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 93:1638–1643
Takanami I (2003) Overexpression of CCR7 mRNA in non-small-cell lung carcinoma: correlation with lymph node metastasis. Int J Cancer 105:186–189
Hirata T, Fukuse T, Naiki H et al (2001) Expression of E-cadherin and lymph node metastasis in resected non-small-cell lung carcinoma. Clin Lung Cancer 3:134–140
Choi YS, Shim YM, Kim SH et al (2003) Prognostic significance of E-cadherin and beta-catenin in resected stage I non-small-cell lung cancer. Eur J Cardio-thorac Surg 24:441–449
Hommura F, Furuuchi K, Yamazaki K et al (2002) Increased expression of beta-catenin predicts better prognosis in non-small-cell lung carcinomas. Cancer 94:752–758
Orlandini M, Semboloni S, Oliviero S (2003) Beta-catenin inversely regulates vascular endothelial growth factor-D mRNA stability. J Biol Chem 278:44650–44656
Stacker SA, Hughes RA, Achen MG (2004) Molecular targeting of lymphatics for therapy. Curr Pharm Des 10:65–74
Cao Y (2005) Emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer 5:735–743
Van Trappen PO, Steele D, Lowe DG, Baithun S, Beasley N, Thiele W, Weich H, Krishnan J, Shepherd JH, Pepper MS, Jackson DG, Sleeman JP, Jacobs IJ (2003) Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201:544–554
Heldin CH, Rubin K, Pietras K, Östman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4:806–813
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Saintigny, P., Morère, JF., Breau, JL. et al. Lymph node metastasis as a new target for cancer treatment. Targ Oncol 2, 49–57 (2007). https://doi.org/10.1007/s11523-006-0037-y
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DOI: https://doi.org/10.1007/s11523-006-0037-y