title: Prox-1 promotes invasion of kaposiform hemangioendotheliomas.
abstract: Kaposi's sarcoma (KS) is the most frequently occurring malignant tumor in patients infected with HIV. Recent studies have revealed that infection of vascular endothelial cells with KS-associated herpes virus in vitro results in a lymphatic reprogramming of these cells, with potent induction of the lymphatic marker genes podoplanin and vascular endothelial growth factor receptor-3, which is mediated by upregulation of the transcription factor Prox1. However, the potential effects of Prox1 expression on the biology of KS and, in particular, on the aggressive and invasive behavior of KS tumors in vivo have remained unknown. We stably expressed Prox1 cDNA in the two mouse hemangioendothelioma cell lines EOMA and Py-4-1, well-established murine models for kaposiform hemangioendothelioma. Surprisingly, we found that expression of Prox1 was sufficient to induce a more aggressive behavior of tumors growing in syngenic mice, leading to enhanced local invasion into the muscular layer and to cellular anaplasia in vivo, and increased migration rate in vitro. This enhanced malignant phenotype was associated with upregulation of several genes involved in proteolysis, cell adhesion, and migration. Together, these results indicate that Prox1 plays an important, previously unanticipated role in mediating the aggressive behavior of vascular neoplasms such as KS.
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Boston, Massachusetts, USA. sdadras@stanford.edu
authors.forename: Soheil S
authors.initials: SS
authors.lastname: Dadras
authors.forename: Adrienne
authors.initials: A
authors.lastname: Skrzypek
authors.forename: Lynh
authors.initials: L
authors.lastname: Nguyen
authors.forename: Jay W
authors.initials: JW
authors.lastname: Shin
authors.forename: Martin M P
authors.initials: MM
authors.lastname: Schulz
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006390:Hemangioendothelioma / Q000235:genetics* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein; D000098853:Podoplanin
chemical_list: D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D000098551:Prospero-Related Homeobox 1 Protein; C490441:Pdpn protein, mouse; D000098853:Podoplanin