The role of lymphangiogenesis and angiogenesis in tumor metastasis

BackgroundMetastasis is the main cause of mortality in cancer patients. Two major routes of cancer cell spread are currently being recognized: dissemination via blood vessels (hematogenous spread) and dissemination via the lymphatic system (lymphogenous spread). Here, our current knowledge on the role of both blood and lymphatic vessels in cancer cell metastasis is summarized. In addition, I will discuss why cancer cells select one or both of the two routes to disseminate and I will provide a short description of the passive and active models of intravasation. Finally, lymphatic vessel density (LVD), blood vessel density (BVD), interstitial fluid pressure (IFP) and tumor hypoxia, as well as regional lymph node metastasis and the recently discovered primo vascular system (PVS) will be highlighted as important factors influencing tumor cell motility and spread and, ultimately, clinical outcome.ConclusionsLymphangiogenesis and angiogenesis are important phenomena involved in the spread of cancer cells and they are associated with a poor prognosis. It is anticipated that new discoveries and advancing knowledge on these phenomena will allow an improvement in the treatment of cancer patients.

[1]  G. Davis,et al.  Biosynthesis, Remodeling, and Functions During Vascular Morphogenesis and Neovessel Stabilization , 2005 .

[2]  M. Pepper,et al.  Lymphangiogenesis and tumor metastasis: myth or reality? , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  B. Mehrara,et al.  HIF‐1α: coordinates lymphangiogenesis during wound healing and in response to inflammation , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  Yaling Tang,et al.  Inflammation linking EMT and cancer stem cells. , 2012, Oral oncology.

[5]  R. Foisner,et al.  E-cadherin regulates cell growth by modulating proliferation-dependent β-catenin transcriptional activity , 2001, The Journal of cell biology.

[6]  R. Ji Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis , 2011, Cellular and Molecular Life Sciences.

[7]  Jing Cai,et al.  PlGF expression in pre‐invasive and invasive lesions of uterine cervix is associated with angiogenesis and lymphangiogenesis , 2009, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[8]  A. Shiotani,et al.  Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma , 2015, PloS one.

[9]  H. Qian,et al.  Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation , 2015, Oncology letters.

[10]  G. Mann,et al.  Targeting lymphangiogenesis to prevent tumour metastasis , 2006, British Journal of Cancer.

[11]  S. Zhang,et al.  Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway. , 2011, International journal of molecular medicine.

[12]  K. Alitalo,et al.  VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. , 2007, Blood.

[13]  M. Skobe,et al.  Lymphatic function, lymphangiogenesis, and cancer metastasis , 2001, Microscopy research and technique.

[14]  Zeng-peng Li,et al.  [Characteristic and clinicopathologic significance of lymphangiogenesis in colorectal cancer]. , 2005, Zhonghua bing li xue za zhi = Chinese journal of pathology.

[15]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[16]  Guillaume Vetter,et al.  Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model , 2013, Scientific Reports.

[17]  M. Detmar,et al.  Pathways Targeting Tumor Lymphangiogenesis , 2006, Clinical Cancer Research.

[18]  S. Stacker,et al.  Focus on lymphangiogenesis in tumor metastasis. , 2005, Cancer cell.

[19]  E. Stanley,et al.  Isolation of human lymphatic endothelial cells by multi-parameter fluorescence-activated cell sorting. , 2015, Journal of visualized experiments : JoVE.

[20]  F. Nedel,et al.  Tumor angiogenesis and lymphangiogenesis: tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms. , 2013, Life sciences.

[21]  P. Sorensen,et al.  E-cadherin cell-cell adhesion in ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. , 2007, Cancer research.

[22]  D. Jackson Lymphatic markers, tumour lymphangiogenesis and lymph node metastasis. , 2007, Cancer treatment and research.

[23]  Ming-Hai Wang,et al.  Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients , 2012, Medical Oncology.

[24]  P. Koopman,et al.  Tumor Lymphangiogenesis as a Potential Therapeutic Target , 2012, Journal of oncology.

[25]  S. Jalkanen,et al.  Different role of CD73 in leukocyte trafficking via blood and lymph vessels. , 2011, Blood.

[26]  M. Shahjahani,et al.  The bone marrow metastasis niche in retinoblastoma , 2015, Cellular Oncology.

[27]  J. Massagué,et al.  TGFβ in Cancer , 2008, Cell.

[28]  H. Alatassi,et al.  Tumor-associated primo vascular system is derived from xenograft, not host. , 2013, Experimental and molecular pathology.

[29]  K. Hirakawa,et al.  Association between Expression of Vascular Endothelial Growth Factor C, Chemokine Receptor CXCR4 and Lymph Node Metastasis in Colorectal Cancer , 2007, Oncology.

[30]  A. Popel,et al.  Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment , 2015, Expert Reviews in Molecular Medicine.

[31]  N. J. Nasser Heparanase involvement in physiology and disease , 2008, Cellular and Molecular Life Sciences.

[32]  V. Yang,et al.  Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours , 2008, BMC Cancer.

[33]  Manran Liu,et al.  Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. , 2015, Cancer letters.

[34]  H. Gårdsvoll,et al.  Targeting a Single Function of the Multifunctional Matrix Metalloprotease MT1-MMP , 2013, The Journal of Biological Chemistry.

[35]  A. Caplan,et al.  Mesenchymal stem cells: mechanisms of inflammation. , 2011, Annual review of pathology.

[36]  H. Sontheimer,et al.  Bradykinin Promotes the Chemotactic Invasion of Primary Brain Tumors , 2011, The Journal of Neuroscience.

[37]  Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report , 2015, Cellular Oncology.

[38]  R. Hynes,et al.  Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide? , 2006, Cell cycle.

[39]  J. Duffield,et al.  Resolved: EMT produces fibroblasts in the kidney. , 2010, Journal of the American Society of Nephrology : JASN.

[40]  R. Croner,et al.  Molecular Mechanisms of Lymphatic Metastasis , 2012 .

[41]  P. An,et al.  Primo vascular system and its potential role in cancer metastasis. , 2013, Advances in experimental medicine and biology.

[42]  Feng Gao,et al.  Low Molecular Weight Hyaluronan Induces Lymphangiogenesis through LYVE-1-Mediated Signaling Pathways , 2014, PloS one.

[43]  Quansheng Zhou,et al.  Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment , 2012, Cancer Microenvironment.

[44]  J. Sleeman,et al.  Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms , 2007, Clinical & Experimental Metastasis.

[45]  A. Wells,et al.  E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas , 2008, Clinical & Experimental Metastasis.

[46]  N. Minagawa,et al.  Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer , 2007, Diseases of the colon and rectum.

[47]  R. Bjerkvig,et al.  Lymphangiogenesis in colorectal cancer—Prognostic and therapeutic aspects , 2007, International journal of cancer.

[48]  J. Banyard,et al.  The role of EMT and MET in cancer dissemination , 2015, Connective tissue research.

[49]  Baocun Sun,et al.  Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis , 2016, Journal of Cancer.

[50]  Nayoun Won,et al.  Evidence for an Additional Metastatic Route: In Vivo Imaging of Cancer Cells in the Primo-Vascular System Around Tumors and Organs , 2011, Molecular Imaging and Biology.

[51]  D. Ribatti,et al.  Crosstalk between angiogenesis and lymphangiogenesis in tumor progression , 2004, Leukemia.

[52]  H. Youn,et al.  Primo vessel as a novel cancer cell migration path from testis with nanoparticle-labeled and GFP expressing cancer cells. , 2013, Journal of acupuncture and meridian studies.

[53]  D. Massi,et al.  The biological significance of lymphangiogenesis in human tumours , 2010 .

[54]  M. Aumailley,et al.  The laminin family , 2013, Cell adhesion & migration.

[55]  Yan Shen,et al.  Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. , 2005, Molecular endocrinology.

[56]  X. Wan,et al.  SHARP1 Suppresses Angiogenesis of Endometrial Cancer by Decreasing Hypoxia-Inducible Factor-1α Level , 2014, PloS one.

[57]  Ying-ying Chen,et al.  BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells , 2014, Cellular Oncology.

[58]  M. Flister,et al.  Lymphangiogenesis and lymphatic metastasis in breast cancer. , 2010, Pathophysiology : the official journal of the International Society for Pathophysiology.

[59]  C. Dai,et al.  Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation , 2011, Molecular Cancer Research.

[60]  Xiaohong Li,et al.  Extracellular matrix protein 1 is correlated to carcinogenesis and lymphatic metastasis of human gastric cancer , 2014, World Journal of Surgical Oncology.

[61]  B. Garmy-Susini,et al.  Integrins in angiogenesis and lymphangiogenesis , 2008, Nature Reviews Cancer.

[62]  S. Fox,et al.  First International Consensus on the Methodology of Lymphangiogenesis Quantification in Solid Human Tumors , 2007 .

[63]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[64]  S. Seidelmann,et al.  Development and pathologies of the arterial wall , 2013, Cellular and Molecular Life Sciences.

[65]  Jun Wang,et al.  Lymphatic microvessel density as a prognostic factor in non-small cell lung carcinoma: a meta-analysis of the literature , 2011, Molecular Biology Reports.

[66]  J. Wilting,et al.  Embryonic development of the lymphovascular system and tumor lymphangiogenesis. , 2007, Cancer treatment and research.

[67]  Xia Zhao,et al.  VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma , 2014, Reproductive Biology and Endocrinology.

[68]  J. Tille,et al.  Lymphangiogenesis and tumor metastasis , 2003, Thrombosis and Haemostasis.

[69]  Hong Zhang,et al.  Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas , 2006, Molecular Cancer.

[70]  K. Chayama,et al.  Expression of hypoxia‐inducible factor‐1α is associated with tumor vascularization in human colorectal carcinoma , 2003, International journal of cancer.

[71]  S. Szala,et al.  [Tumor blood vessels]. , 2011, Postepy higieny i medycyny doswiadczalnej.

[72]  B. Ksander,et al.  A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice. , 2015, Investigative ophthalmology & visual science.

[73]  S. Hirakawa From tumor lymphangiogenesis to lymphvascular niche , 2009, Cancer science.

[74]  S. Nathanson,et al.  Preclinical models of regional lymph node tumor metastasis. , 2007, Cancer treatment and research.

[75]  S. Suh,et al.  Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway , 2014, Cellular Oncology.

[76]  O. Colegio,et al.  Lymphangiogenesis linked to VEGF-C from tumor-associated macrophages: accomplices to metastasis by cutaneous squamous cell carcinoma? , 2011, The Journal of investigative dermatology.

[77]  J. Meléndez-Zajgla,et al.  NF-κB signaling in cancer stem cells: a promising therapeutic target? , 2015, Cellular Oncology.

[78]  W. Hohenberger,et al.  Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract. , 2012, International journal of clinical and experimental pathology.

[79]  A. South,et al.  Tumour-stroma crosstalk in the development of squamous cell carcinoma. , 2014, The international journal of biochemistry & cell biology.

[80]  S. Amatschek,et al.  Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. , 2007, Blood.

[81]  Michael Detmar,et al.  Tumor and lymph node lymphangiogenesis—impact on cancer metastasis , 2006, Journal of leukocyte biology.

[82]  Hyo-Jong Lee,et al.  Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway , 2015, Cellular Oncology.

[83]  A. Joussen,et al.  Expression of haematogenous and lymphogenous chemokine receptors and their ligands on uveal melanoma in association with liver metastasis , 2012, Acta ophthalmologica.

[84]  Ronald T Raines,et al.  Collagen structure and stability. , 2009, Annual review of biochemistry.

[85]  M. Sixt,et al.  Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels , 2009, The Journal of experimental medicine.

[86]  I. Fidler,et al.  Impact of sentinel lymphadenectomy on survival in a murine model of melanoma , 2008, Clinical & Experimental Metastasis.

[87]  R. Matkowski,et al.  Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer--10 years follow-up analysis. , 2007, Anticancer research.

[88]  H. Grabsch,et al.  Tumour-microenvironment interactions: role of tumour stroma and proteins produced by cancer-associated fibroblasts in chemotherapy response , 2013, Cellular Oncology.

[89]  A. Rajasekaran,et al.  Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. , 2006, Cancer research.

[90]  W. Jiang,et al.  KAI-1/CD82, the molecule and clinical implication in cancer and cancer metastasis. , 2009, Histology and histopathology.

[91]  S. Fox,et al.  First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours , 2006, British Journal of Cancer.

[92]  Yibin Kang,et al.  Targeting tumor-stromal interactions in bone metastasis. , 2014, Pharmacology & therapeutics.

[93]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[94]  S. Leong,et al.  Cancer metastasis and the lymphovascular system : basis for rational therapy , 2007 .

[95]  K. Alitalo,et al.  Role of lymphangiogenic factors in tumor metastasis. , 2004, Biochimica et biophysica acta.

[96]  Zhuang Wu,et al.  Tumor lymphangiogenesis and lymphangiogenic growth factors. , 2008, Archives of medical research.

[97]  M. Nieto,et al.  Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. , 2012, Cancer cell.

[98]  M. Abdel-Hadi,et al.  Lymphatic vessel density as prognostic factor in breast carcinoma: relation to clinicopathologic parameters. , 2009, Journal of the Egyptian National Cancer Institute.

[99]  Michael Elkin,et al.  Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. , 2006, The international journal of biochemistry & cell biology.

[100]  A. Jacomo,et al.  Anatomy of the human lymphatic system. , 2007, Cancer treatment and research.

[101]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[102]  Z. Werb,et al.  The extracellular matrix: A dynamic niche in cancer progression , 2012, The Journal of cell biology.

[103]  Z. Werb,et al.  Regulation of matrix biology by matrix metalloproteinases. , 2004, Current opinion in cell biology.

[104]  P. Hewett,et al.  Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. , 2002, Cancer research.

[105]  G. G. Van den Eynden,et al.  Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: systematic review and meta‐analysis , 2014, The British journal of dermatology.

[106]  T. Yoneda,et al.  Cellular fibronectin 1 promotes VEGF-C expression, lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma , 2015, Clinical & Experimental Metastasis.

[107]  Min Wu,et al.  The effect of interstitial pressure on tumor growth: coupling with the blood and lymphatic vascular systems. , 2013, Journal of theoretical biology.

[108]  Jun Wang,et al.  Lymphatic microvessel density and vascular endothelial growth factor-C and -D as prognostic factors in breast cancer: a systematic review and meta-analysis of the literature , 2012, Molecular Biology Reports.

[109]  Zhiwei Wang,et al.  Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. , 2013, Biochimica et biophysica acta.

[110]  K. Takabe,et al.  Lymphangiogenesis: a new player in cancer progression. , 2010, World journal of gastroenterology.

[111]  S. Stacker,et al.  The role of tumor lymphangiogenesis in metastatic spread , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[112]  Hiroyuki Tomita,et al.  Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. , 2011, Cancer cell.

[113]  S. Hidaka,et al.  Expressions of Vascular Endothelial Growth Factor (VEGF)-D and VEGF Receptor-3 in Colorectal Cancer: Relationship to Lymph Node Metastasis , 2002 .

[114]  W. Jiang,et al.  Lymphangiogenesis and cancer metastasis. , 2011, Frontiers in bioscience.

[115]  I. Ellis,et al.  Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis , 2007, British Journal of Cancer.

[116]  J. Reis-Filho,et al.  Lymphangiogenesis in tumors: What do we know? , 2003, Microscopy research and technique.

[117]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[118]  H. Kim,et al.  Primo Vascular System Accompanying a Blood Vessel from Tumor Tissue and a Method to Distinguish It from the Blood or the Lymph System , 2013, Evidence-based complementary and alternative medicine : eCAM.

[119]  R. D. de Waal,et al.  Lymphangiogenesis in malignant tumours: does it occur? , 2001, The Journal of pathology.

[120]  C. Kainz,et al.  Prognostic value of CD44 splice variants in human stage III cervical cancer. , 1995, European journal of cancer.

[121]  D. Jackson,et al.  LYVE-1, the lymphatic system and tumor lymphangiogenesis. , 2001, Trends in immunology.

[122]  R. Ji Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. , 2014, Cancer letters.

[123]  Carla Danussi,et al.  Vasculature Functional Defects of Lymphatic Deficiency Causes Structural and Emilin1 , 2008 .

[124]  B. Zetter,et al.  Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer , 2014, BMC Cancer.

[125]  G. Semenza Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis , 2013, Oncogene.

[126]  Rakesh K Jain,et al.  Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed? , 2007, The Lancet. Oncology.

[127]  Pu Chen,et al.  Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: A computational model. , 2015, Microvascular research.

[128]  R. Ji Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: New insights into intratumoral and peritumoral lymphatics , 2006, Cancer and Metastasis Reviews.

[129]  Y. Kapila,et al.  An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK , 2007, Apoptosis.

[130]  P. V. van Dam,et al.  Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer , 2007, The Journal of pathology.

[131]  Yibin Kang,et al.  The metastasis-promoting roles of tumor-associated immune cells , 2013, Journal of Molecular Medicine.

[132]  Jun Zhou,et al.  Tumor‐associated macrophages induce lymphangiogenesis in cervical cancer via interaction with tumor cells , 2014, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[133]  Melody A Swartz,et al.  Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. , 2004, Microvascular research.

[134]  N. Cheville Ultrastructural Pathology: The Comparative Cellular Basis of Disease , 2009 .

[135]  S. Zou,et al.  Effect of serum interleukin 21 on the development of coronary artery disease , 2014, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[136]  Lei Zhou,et al.  Clinicopathological significance of KAI1 expression and epithelial-mesenchymal transition in non-small cell lung cancer , 2015, World Journal of Surgical Oncology.

[137]  Robert V Farese,et al.  Fatal Bilateral Chylothorax in Mice Lacking the Integrin α9β1 , 2000, Molecular and Cellular Biology.

[138]  W. Eisterer,et al.  CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor. , 1995, Blood.

[139]  J. Sleeman,et al.  Tumor-induced lymphangiogenesis: a target for cancer therapy? , 2006, Journal of biotechnology.

[140]  Jie Cheng,et al.  α-Smooth muscle actin-positive myofibroblasts, in association with epithelial-mesenchymal transition and lymphogenesis, is a critical prognostic parameter in patients with oral tongue squamous cell carcinoma. , 2014, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[141]  Giacomo Azzali,et al.  On the transendothelial passage of tumor cell from extravasal matrix into the lumen of absorbing lymphatic vessel. , 2006, Microvascular research.

[142]  Ajit S Narang,et al.  Role of tumor vascular architecture in drug delivery. , 2011, Advanced drug delivery reviews.

[143]  Jing Yang,et al.  Epithelial–mesenchymal plasticity in carcinoma metastasis , 2013, Genes & development.

[144]  Jingtai Cao,et al.  VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. , 2004, The Journal of clinical investigation.

[145]  K. Alitalo,et al.  Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. , 2002, Journal of the National Cancer Institute.