Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma

The invasion of lymphatic vessels by colorectal cancer (CRC) and its subsequent spread to draining lymph nodes is a key determinant of prognosis in this common and frequently fatal malignancy. Although tumoural lymphangiogenesis is assumed to contribute to this process, review of the current literature fails to support any notion of a simple correlation between lymphatic vessel density and CRC metastasis. Furthermore, attempts to correlate the expression of various lymphangiogenic growth factors, most notably VEGF‐C and VEGF‐D, with the lymphatic metastasis of CRC have provided contradictory results. Recent evidence from animal and human models of tumour metastasis suggests that complex functional and biochemical interactions between the microvasculature of tumours and other cell types within the tumour microenvironment may play a pivotal role in the behaviour of commonly metastasizing tumours. Indeed, previous insights into tumoural blood vessels have provided candidate markers of tumoural angiogenesis that are currently the subject of intense investigation as future therapeutic targets. In this review article we survey the current evidence relating lymphangiogenesis and lymphangiogenic growth factor production to metastasis by CRC, and attempt to provide some insight into the apparent discrepancies within the literature. In particular, we also discuss some new and provocative insights into the properties of tumoural lymphatics suggesting that they have specific expression profiles distinct from those of normal lymphatic vessels and that appear to promote metastasis. These findings raise the exciting prospect of future biomarkers of lymphatic metastasis and identify potential targets for new generation anti‐tumour therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  P. Gruss,et al.  Prox 1, a prospero-related homeobox gene expressed during mouse development , 1993, Mechanisms of Development.

[2]  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.

[3]  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.

[4]  R. Nibbs,et al.  Cloning and Characterization of a Novel Promiscuous Human β-Chemokine Receptor D6* , 1997, The Journal of Biological Chemistry.

[5]  K. Alitalo,et al.  VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. , 1997, Developmental biology.

[6]  R. Jain,et al.  Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. , 1997, Science.

[7]  D. Jackson,et al.  LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan , 1999, The Journal of cell biology.

[8]  H. Kowalski,et al.  [Podoplanin--a specific marker for lymphatic endothelium expressed in angiosarcoma]. , 1999, Verhandlungen der Deutschen Gesellschaft fur Pathologie.

[9]  K. Alitalo,et al.  Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors , 1999, Cancer.

[10]  B. Brooke,et al.  Defective angiogenesis in mice lacking endoglin. , 1999, Science.

[11]  K. Alitalo,et al.  VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. , 1999, The American journal of pathology.

[12]  K. Kinzler,et al.  Genes expressed in human tumor endothelium. , 2000, Science.

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

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

[15]  E C Nice,et al.  Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF‐C/D receptor VEGFR‐3 , 2001, The EMBO journal.

[16]  S. Eccles,et al.  VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. , 2001, Neoplasia.

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

[18]  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.

[19]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

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

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

[22]  T. Veikkola,et al.  Signalling via vascular endothelial growth factor receptor‐3 is sufficient for lymphangiogenesis in transgenic mice , 2001, The EMBO journal.

[23]  C. Wahlestedt,et al.  Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

[25]  K. Chayama,et al.  Clinical Significance of Vascular Endothelial Growth Factor C Expression and Angiogenesis at the Deepest Invasive Site of Advanced Colorectal Carcinoma , 2002, Oncology.

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

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

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

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

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

[31]  P. Campochiaro,et al.  Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. , 2002, Developmental cell.

[32]  K. Alitalo,et al.  Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  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.

[34]  K. Chayama,et al.  Clinical Significance of Angiogenic Factor Expression at the Deepest Invasive Site of Advanced Colorectal Carcinoma , 2002, Oncology.

[35]  Stephen B Fox,et al.  The angiogenic switch for vascular endothelial growth factor (VEGF)‐A, VEGF‐B, VEGF‐C, and VEGF‐D in the adenoma–carcinoma sequence during colorectal cancer progression , 2003, The Journal of pathology.

[36]  M. Yashiro,et al.  Correlation Between Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis in T1 Carcinoma of the Colon and Rectum , 2003, Surgery Today.

[37]  K. Hirata,et al.  Quantification of vascular endothelial growth factor-C and its receptor-3 messenger RNA with real-time quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer. , 2003, Surgery.

[38]  J. Sleeman,et al.  Expression of vascular endothelial growth factor (VEGF)‐C and VEGF‐D, and their receptor VEGFR‐3, during different stages of cervical carcinogenesis , 2003, The Journal of pathology.

[39]  A. Harris,et al.  Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer , 2003, The Journal of pathology.

[40]  M. Ohno,et al.  Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer. , 2003, Oncology reports.

[41]  K. Hirata,et al.  Expression analysis of vascular endothelial growth factors and their relationships to lymph node metastasis in human colorectal cancer. , 2003, Journal of experimental & clinical cancer research : CR.

[42]  Michael Detmar,et al.  Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. , 2003, The American journal of pathology.

[43]  C. Compton,et al.  The Prognosis of T3N0 Colon Cancer Is Dependent on the Number of Lymph Nodes Examined , 2003, Annals of Surgical Oncology.

[44]  W. Jiang,et al.  Quantitative analysis of lymphangiogenic markers in human colorectal cancer. , 2003, International journal of oncology.

[45]  Y. Kimura,et al.  Epiadryamicin concentration in experimental hepatic metastases after bolus or continous infusion through systemic or locoregional routes. , 2003 .

[46]  M. Kayahara,et al.  Expression of Vascular Endothelial Growth Factor D Is Associated with Lymph Node Metastasis in Human Colorectal Carcinoma , 2003, Oncology.

[47]  L. Akslen,et al.  Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  Toshio Ohhashi,et al.  PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. , 2004, Cancer cell.

[49]  K. Kinzler,et al.  TEM8 Interacts with the Cleaved C5 Domain of Collagen α3(VI) , 2004, Cancer Research.

[50]  K. Kinzler,et al.  TEM8 interacts with the cleaved C5 domain of collagen alpha 3(VI). , 2004, Cancer research.

[51]  C. Compton,et al.  The Staging of Colorectal Cancer: 2004 and Beyond , 2004, CA: a cancer journal for clinicians.

[52]  P. Alken,et al.  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). , 2004, The Journal of urology.

[53]  Rakesh K. Jain,et al.  Pathology: Cancer cells compress intratumour vessels , 2004, Nature.

[54]  D. Bates,et al.  Lymphatic density and metastatic spread in human malignant melanoma , 2004, British Journal of Cancer.

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

[56]  P. Heikkilä,et al.  High LYVE-1–Positive Lymphatic Vessel Numbers Are Associated with Poor Outcome in Breast Cancer , 2004, Clinical Cancer Research.

[57]  K. Chayama,et al.  Regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma. , 2004, European journal of cancer.

[58]  D. Massi,et al.  Tumor lymphangiogenesis in head and neck squamous cell carcinoma , 2004, Cancer.

[59]  P. Bohlen,et al.  VEGF‐A promotes tissue repair‐associated lymphatic vessel formation via VEGFR‐2 and the α1β1 and α2β1 integrins , 2004 .

[60]  K. Kinzler,et al.  Identification of a Binding Partner for the Endothelial Cell Surface Proteins TEM7 and TEM7R , 2004, Cancer Research.

[61]  M. Maio,et al.  Highlights on endoglin (CD105): from basic findings towards clinical applications in human cancer , 2004, Journal of Translational Medicine.

[62]  K. Chayama,et al.  Expression of VEGF‐C and VEGF‐D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma , 2004, Cancer science.

[63]  Yitao Jia,et al.  Expression of vascular endothelial growth factor-C and the relationship between lymphangiogenesis and lymphatic metastasis in colorectal cancer. , 2004, World journal of gastroenterology.

[64]  T. Bando,et al.  Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma , 2004, Laboratory Investigation.

[65]  P. Kyzas,et al.  Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma , 2005, The Journal of pathology.

[66]  S. Hirakawa,et al.  Hepatocyte growth factor promotes lymphatic vessel formation and function , 2005, The EMBO journal.

[67]  D. Zawieja,et al.  Microarray analysis of VEGF-C responsive genes in human lymphatic endothelial cells. , 2005, Lymphatic research and biology.

[68]  K. Alitalo,et al.  Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. , 2005, Blood.

[69]  K. Alitalo,et al.  Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. , 2005, Blood.

[70]  Yihai Cao,et al.  Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[72]  K. Alitalo,et al.  Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. , 2005, Cancer research.

[73]  Xiaowei Xu,et al.  Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix , 2005, Clinical Cancer Research.

[74]  Yihai Cao,et al.  Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. , 2005, Cancer research.

[75]  J. Tímár,et al.  Lymphangiogenesis Correlates with Lymph Node Metastasis, Prognosis, and Angiogenic Phenotype in Human Non–Small Cell Lung Cancer , 2005, Clinical Cancer Research.

[76]  W. Hohenberger,et al.  Prediction of lymph node metastasis in colorectal carcinoma by expressionof chemokine receptor CCR7 , 2005, International journal of cancer.

[77]  D. Jackson,et al.  An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium , 2006, The Journal of experimental medicine.

[78]  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.

[79]  C. Magi-Galluzzi,et al.  Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma , 2006, Modern Pathology.

[80]  S. Butz,et al.  ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability , 2006, The Journal of experimental medicine.

[81]  Y. Wang,et al.  Expression and quantification of LYVE-1 in human colorectal cancer , 2006, Clinical and Experimental Medicine.

[82]  D. Hanahan,et al.  Lymphatic zip codes in premalignant lesions and tumors. , 2006, Cancer research.

[83]  A. Hansen,et al.  Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. , 2006, Blood.

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

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

[86]  P. Alken,et al.  The role of the lymphatic system and its specific growth factor, vascular endothelial growth factor C, for lymphogenic metastasis in prostate cancer , 2006, BJU international.

[87]  K. Ohba,et al.  Lymphangiogenesis and Angiogenesis in Bladder Cancer: Prognostic Implications and Regulation by Vascular Endothelial Growth Factors-A, -C, and -D , 2006, Clinical Cancer Research.

[88]  M. Skobe,et al.  Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. , 2006, Cancer research.

[89]  Yung-Chi Hou,et al.  Expression and prognostic significance of angiopoietin in colorectal carcinoma , 2006, Journal of surgical oncology.

[90]  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.

[91]  G. Motohashi,et al.  Increased density and diameter of lymphatic microvessels correlate with lymph node metastasis in early stage invasive colorectal carcinoma , 2006, Virchows Archiv.

[92]  A. Sézeur,et al.  Pathology Underrates Colon Cancer Extranodal and Nodal Metastases; Ex vivo Radioimmunodetection Helps Staging , 2007, Clinical Cancer Research.

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

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

[95]  K. Chayama,et al.  Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer , 2007, Diseases of the colon and rectum.

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

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

[98]  Yihai Cao,et al.  Tumor-derived lymphangiogenic factors and lymphatic metastasis. , 2007, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[99]  Y. Kawai,et al.  Immunohistochemical demonstration of proliferating lymphatic vessels in colorectal carcinoma and its clinicopathological significance. , 2007, Cancer letters.

[100]  T. Manabe,et al.  Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes , 2007, Oncogene.

[101]  S. Yuan,et al.  Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism. , 2007, American journal of physiology. Heart and circulatory physiology.

[102]  R. Montironi,et al.  Lymphatic vessel density in radical prostatectomy specimens. , 2008, Human pathology.

[103]  D. McDonald,et al.  Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. , 2008, Genes & development.

[104]  A. Horiguchi,et al.  Prediction of lymphatic invasion by peritumoral lymphatic vessel density in prostate biopsy cores , 2008, The Prostate.

[105]  Yihai Cao,et al.  A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. , 2008, Cancer research.

[106]  P. Alken,et al.  Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. , 2008, European urology.

[107]  R. Eği̇lmez,et al.  The intratumoral microvessel density and expression of bFGF and nm23-Hl in colorectal cancer , 2008, Pathology & Oncology Research.

[108]  S. Stacker,et al.  Molecular Control of Lymphatic Metastasis , 2008, Annals of the New York Academy of Sciences.

[109]  M. Winslet.  Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach , 2009 .