title: Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin.
abstract: The membrane glycoprotein podoplanin is expressed by several types of human cancers and might be associated with their malignant progression. Its exact biological function and molecular targets are unclear, however. Here, we assessed the relevance of tumor cell expression of podoplanin in cancer metastasis to lymph nodes, using a human MCF7 breast carcinoma xenograft model. We found that podoplanin expression promoted tumor cell motility in vitro and, unexpectedly, increased tumor lymphangiogenesis and metastasis to regional lymph nodes in vivo, without promoting primary tumor growth. Importantly, high cancer cell expression levels of podoplanin correlated with lymph node metastasis and reduced survival times in a large cohort of 252 oral squamous cell carcinoma patients. Based on comparative transcriptional profiling of tumor xenografts, we identified endothelin-1, villin-1, and tenascin-C as potential mediators of podoplanin-induced tumor lymphangiogenesis and metastasis. These unexpected findings identify a novel mechanism of tumor lymphangiogenesis and metastasis induced by cancer cell expression of podoplanin, suggesting that reagents designed to interfere with podoplanin function might be developed as therapeutics for patients with advanced cancer.
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Leah N
authors.initials: LN
authors.lastname: Cueni
authors.forename: Ivan
authors.initials: I
authors.lastname: Hegyi
authors.forename: Jay W
authors.initials: JW
authors.lastname: Shin
authors.forename: Andrea
authors.initials: A
authors.lastname: Albinger-Hegyi
authors.forename: Silke
authors.initials: S
authors.lastname: Gruber
authors.forename: Rainer
authors.initials: R
authors.lastname: Kunstfeld
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014183:Transplantation, Heterologous; D000098853:Podoplanin
chemical_list: D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D008562:Membrane Glycoproteins; C117468:PDPN protein, human; D000098853:Podoplanin