Lymphatic Vessel Activation in Cancer

Most cancerous lesions metastasize through the lymphatic system and the status of regional lymph nodes is the most important indicator of a patient's prognosis. The extent of lymph node involvement with cancer is also an important parameter used for determining treatment options. Although the importance of the lymphatic system for metastasis has been well recognized, traditionally, the lymphatic vessels have not been considered actively involved in the metastatic process. Recent evidence, however, indicates that the activation of the lymphatic system is an important factor in tumor progression to metastasis. Tumor lymphangiogenesis has been associated with increased propensity for metastasis, and lymphatic vessel density has emerged as another promising prognostic indicator. More recently, lymphangiogenesis in the sentinel lymph nodes has been shown to contribute to malignant progression. In addition to its role as a transport system for tumor cells, the lymphatic system may also be more actively involved in metastases by directly facilitating tumor cell recruitment into the lymphatic vessels. This review highlights recent advances in our understanding of the mechanisms by which lymphatic vessels participate in metastasis.

[1]  I. Werner Medical Therapy of Breast Cancer , 2008 .

[2]  A. Ruddell,et al.  p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis , 2008, Oncogene.

[3]  K. Miyazono,et al.  Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. , 2007, Cancer research.

[4]  E. van Marck,et al.  Increased Sentinel Lymph Node Lymphangiogenesis is Associated with Nonsentinel Axillary Lymph Node Involvement in Breast Cancer Patients with a Positive Sentinel Node , 2007, Clinical Cancer Research.

[5]  R. Nibbs,et al.  The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. , 2007, The Journal of clinical investigation.

[6]  S. Lo,et al.  Survival predictors in patients with node‐negative gastric carcinoma , 2007, Journal of gastroenterology and hepatology.

[7]  J. Nährig,et al.  Sentinel Lymph Node Biopsy in Colon Cancer: A Prospective Multicenter Trial , 2007, Annals of surgery.

[8]  D. Bates,et al.  Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis , 2007, Oncogene.

[9]  L. Forrest,et al.  Prediction in breast cancer of the extent of axillary node involvement from the size and lymphovascular invasion status of the primary tumour: medico-legal considerations. , 2007, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[10]  T. Veikkola,et al.  Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. , 2007, The American journal of pathology.

[11]  N. Baxter,et al.  Association versus causation versus quality improvement: setting benchmarks for lymph node evaluation in colon cancer. , 2007, Journal of the National Cancer Institute.

[12]  M. May,et al.  Prognostic impact of lymphovascular invasion in radical prostatectomy specimens , 2007, BJU international.

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

[14]  A. Ruddell,et al.  Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. , 2007, The American journal of pathology.

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

[16]  B. Berghuis,et al.  Preparing the "soil": the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. , 2006, Cancer research.

[17]  M. Rivera,et al.  Issues Relating to Lymphovascular Invasion in Breast Carcinoma , 2006, Advances in anatomic pathology.

[18]  E. van Marck,et al.  Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer , 2006, British Journal of Cancer.

[19]  R. Elashoff,et al.  Sentinel-node biopsy or nodal observation in melanoma. , 2006, The New England journal of medicine.

[20]  Dai Fukumura,et al.  Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. , 2006, Cancer research.

[21]  I. Thompson,et al.  Current status of lymph node‐positive prostate cancer , 2006, Cancer.

[22]  M. Gnant,et al.  VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. , 2006, Surgery.

[23]  Y. Lotan,et al.  Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Jen-Hao Chen,et al.  Nodal dissection for patients with gastric cancer: a randomised controlled trial. , 2006, The Lancet. Oncology.

[25]  F. Ginhoux,et al.  B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. , 2006, Immunity.

[26]  R W Blamey,et al.  Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma. , 2006, European journal of cancer.

[27]  J. Listgarten,et al.  Lymphovascular Invasion Is Associated With Poor Survival in Gastric Cancer: An Application of Gene-Expression and Tissue Array Techniques , 2006, Annals of Surgery.

[28]  Haiqun Lin,et al.  Lymphovascular invasion is an independent prognostic factor in prostatic adenocarcinoma. , 2005, The Journal of urology.

[29]  D. Kerjaschki The crucial role of macrophages in lymphangiogenesis. , 2005, The Journal of clinical investigation.

[30]  Yihai Cao Emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis , 2005, Nature Reviews Cancer.

[31]  Jinping Li,et al.  Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway , 2005, Oncogene.

[32]  S. Groshen,et al.  Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. , 2005, The Journal of urology.

[33]  B. Konety,et al.  Effect of axillary lymphadenectomy on breast carcinoma survival , 2005, Breast Cancer Research and Treatment.

[34]  Satoshi Hirakawa,et al.  VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis , 2005, The Journal of experimental medicine.

[35]  Antonio Alcami,et al.  The chemokine receptor D6 limits the inflammatory response in vivo , 2005, Nature Immunology.

[36]  K. Alitalo,et al.  Loss of Neural Cell Adhesion Molecule Induces Tumor Metastasis by Up-regulating Lymphangiogenesis , 2004, Cancer Research.

[37]  Dai Fukumura,et al.  Peritumor Lymphatics Induced by Vascular Endothelial Growth Factor-C Exhibit Abnormal Function , 2004, Cancer Research.

[38]  D. Gouma,et al.  Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[40]  P. Heikkilä,et al.  Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium. , 2003, Cancer research.

[41]  Donglei Zhang,et al.  Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. , 2003, Cancer research.

[42]  S. Jalkanen,et al.  The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels , 2003, European journal of immunology.

[43]  J. Sleeman,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. , 2003, Cancer research.

[44]  M. Skobe,et al.  Therapeutic lymphangiogenesis with human recombinant VEGF‐C , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  M. Skobe,et al.  Lymphatic Vessel Activation in Cancer , 2002, Annals of the New York Academy of Sciences.

[46]  M. Skobe,et al.  Molecular characterization of lymphatic endothelial cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  I. Olivotto,et al.  Age-related variations in the use of axillary dissection: a survival analysis of 8038 women with T1-ST2 breast cancer. , 2002, International journal of radiation oncology, biology, physics.

[48]  M. Karkkainen,et al.  Abnormal lymphatic vessel development in neuropilin 2 mutant mice. , 2002, Development.

[49]  K. Alitalo,et al.  Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox‐1 homeobox transcription factor , 2002, The EMBO journal.

[50]  K. Alitalo,et al.  Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. , 2002, The American journal of pathology.

[51]  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.

[52]  R. Jain,et al.  Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. , 2002, Journal of the National Cancer Institute.

[53]  Rakesh K Jain,et al.  Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics , 2002, Science.

[54]  K. Alitalo,et al.  VEGF‐C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF‐7 tumors , 2002, International journal of cancer.

[55]  M. Detmar,et al.  An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype , 2002, The EMBO journal.

[56]  R. Jain,et al.  Intratumoral lymphatic vessels: a case of mistaken identity or malfunction? , 2002, Journal of the National Cancer Institute.

[57]  Adrian L Harris,et al.  Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. , 2002, Cancer research.

[58]  R. Jain,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. , 2001, Cancer Research.

[59]  H. Wiley,et al.  Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. , 2001, Journal of the National Cancer Institute.

[60]  S. Jalkanen,et al.  Mannose Receptor Is a Novel Ligand for L-Selectin and Mediates Lymphocyte Binding to Lymphatic Endothelium , 2001, The Journal of experimental medicine.

[61]  J. Sleeman,et al.  Markers for the lymphatic endothelium: In search of the holy grail? , 2001, Microscopy research and technique.

[62]  J. Sleeman,et al.  Interaction of rat tumor cells with blood vessels and lymphatics of the avian chorioallantoic membrane , 2001, Microscopy research and technique.

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

[64]  R. Kauppinen,et al.  A model for gene therapy of human hereditary lymphedema , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[65]  D. Kerjaschki,et al.  Isolation and Characterization of Dermal Lymphatic and Blood Endothelial Cells Reveal Stable and Functionally Specialized Cell Lineages , 2001, The Journal of experimental medicine.

[66]  M. Skobe,et al.  Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. , 2001, The American journal of pathology.

[67]  M. Nosrati,et al.  Vascular involvement in the prognosis of primary cutaneous melanoma. , 2001, Archives of dermatology.

[68]  T. Furuhata,et al.  Vascular endothelial growth factor C promotes human gastric carcinoma lymph node metastasis in mice. , 2001, Journal of experimental & clinical cancer research : CR.

[69]  J. Brierley,et al.  Local excision and postoperative radiotherapy for distal rectal cancer. , 2001, International journal of radiation oncology, biology, physics.

[70]  S. Breiteneder-Geleff,et al.  Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. , 2001, Anticancer research.

[71]  D. Ruiter,et al.  Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma. , 2001, Investigative ophthalmology & visual science.

[72]  D. Kerjaschki,et al.  The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. , 2001, The American journal of pathology.

[73]  L. Orci,et al.  Vascular endothelial growth factor‐C‐mediated lymphangiogenesis promotes tumour metastasis , 2001, The EMBO journal.

[74]  Steven A. Stacker,et al.  VEGF-D promotes the metastatic spread of tumor cells via the lymphatics , 2001, Nature Medicine.

[75]  Thomas Hawighorst,et al.  Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis , 2001, Nature Medicine.

[76]  P. Tanis,et al.  History of sentinel node and validation of the technique , 2001, Breast Cancer Research.

[77]  M. Schindl,et al.  Lymphatic microvessel density as a novel prognostic factor in early‐stage invasive cervical cancer , 2001, International journal of cancer.

[78]  G. Martiny-Baron,et al.  Active interaction of human A375 melanoma cells with the lymphatics in vivo , 2000, Histochemistry and Cell Biology.

[79]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[80]  Y. Maehara,et al.  Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues , 2000, British Journal of Cancer.

[81]  M. Schindl,et al.  Lymphatic microvessel density in epithelial ovarian cancer: its impact on prognosis. , 2000, Anticancer research.

[82]  R. Jain,et al.  Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. , 2000, Cancer research.

[83]  S. Hirohashi,et al.  Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[84]  A. Eggert,et al.  High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[85]  J. Vaillant,et al.  Vegf, vegf‐B, vegf‐C and their receptors KDR, FLT‐1 and FLT‐4 during the neoplastic progression of human colonic mucosa , 2000, International journal of cancer.

[86]  D. Birnbaum,et al.  VEGFc and VEGFR3 expression in human thyroid pathologies , 2000, International journal of cancer.

[87]  M. Oda,et al.  Increased vascular endothelial growth factor and vascular endothelial growth factor-c and decreased nm23 expression associated with microdissemination in the lymph nodes in stage I non-small cell lung cancer. , 2000, The Journal of thoracic and cardiovascular surgery.

[88]  T. Obara,et al.  Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas. , 1999, Surgery.

[89]  L. Mariani,et al.  Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. , 1999, The American journal of pathology.

[90]  T. Kawarabayashi,et al.  The grading of lymphovascular space invasion in endometrial carcinoma , 1999, Cancer.

[91]  R. K. Bright,et al.  VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours , 1999, British Journal of Cancer.

[92]  J. Kurebayashi,et al.  Expression of Vascular Endothelial Growth Factor (VEGF) Family Members in Breast Cancer , 1999, Japanese journal of cancer research : Gann.

[93]  Takuma Sasaki,et al.  Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[94]  K. Alitalo,et al.  Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis , 1999, British Journal of Cancer.

[95]  K. Alitalo,et al.  Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. , 1998, The American journal of pathology.

[96]  E. Tschachler,et al.  Lymphatic endothelium and Kaposi's sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. , 1998, Cancer research.

[97]  K. Alitalo,et al.  Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[98]  S. Ergün,et al.  Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia , 1997, Leukemia.

[99]  Yihai Cao,et al.  Proteolytic processing regulates receptor specificity and activity of VEGF‐C , 1997, The EMBO journal.

[100]  K. Alitalo,et al.  Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia , 1997, Oncogene.

[101]  L. Akslen,et al.  Independent prognostic importance of vascular invasion in nodular melanomas , 1996, Cancer.

[102]  Benoit Vf Clinical problem-solving: if at first you don't succeed. , 1996 .

[103]  W. Wood,et al.  Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[104]  K. Alitalo,et al.  Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[105]  B. Zetter,et al.  Adhesion molecules in tumor metastasis. , 1993, Seminars in cancer biology.

[106]  D L Morton,et al.  Technical details of intraoperative lymphatic mapping for early stage melanoma. , 1992, Archives of surgery.

[107]  L. Liotta,et al.  Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation , 1991, Cell.

[108]  Rakesh K. Jain,et al.  Vascular and interstitial barriers to delivery of therapeutic agents in tumors , 1990, Cancer and Metastasis Reviews.

[109]  G. Schmid-Schönbein,et al.  Microlymphatics and lymph flow. , 1990, Physiological reviews.

[110]  F. Hartveit Attenuated cells in breast stroma: the missing lymphatic system of the breast , 1990, Histopathology.

[111]  T. Ryan,et al.  Structure and function of lymphatics. , 1989, The Journal of investigative dermatology.

[112]  Geert W. Schmid-Schönbein,et al.  Biomechanical interactions of cancer cells with the microvasculature during metastasis , 1989, Cell Biophysics.

[113]  L. Leak Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. , 1970, Microvascular research.

[114]  I. Zeidman Experimental studies on the spread of cancer in the lymphatic system. III. Tumor emboli in thoracic duct; the pathogenesis of Virchow's node. , 1955, Cancer research.

[115]  R. Gilchrist,et al.  Surgical management of advanced cancer of the breast. , 1950, A.M.A. archives of surgery.

[116]  R. Tilghman,et al.  LYMPH VESSELS IN RABBIT CARCINOMA: WITH A NOTE ON THE NORMAL LYMPH VESSEL STRUCTURE OF THE TESTIS , 1933 .

[117]  F. L. Reichert THE REGENERATION OF THE LYMPHATICS , 1926 .

[118]  J. Kim,et al.  Genetic and Pathologic Changes associated with Lymphovascular Invasion of Colorectal Adenocarcinoma , 2005, Clinical & Experimental Metastasis.

[119]  M. Witte,et al.  Lymphangiogenesis: mechanisms, significance and clinical implications. , 1997, EXS.

[120]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. , 1996, The EMBO journal.

[121]  C. Balch The role of elective lymph node dissection in melanoma: rationale, results, and controversies. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.