title: Vascular endothelial growth factor c promotes ovarian carcinoma progression through paracrine and autocrine mechanisms.
abstract: Vascular endothelial growth factor C (VEGFC) has been reported to promote tumor progression in several tumor types, mainly through the stimulation of lymphangiogenesis and lymphatic metastasis. However, the expression and biological significance of the VEGFC/VEGF receptor (VEGFR)-3 pathway in ovarian cancer growth and dissemination are unclear, and have been investigated in this study. Soluble VEGFC was detected in the plasma and ascites of patients with ovarian carcinoma, and VEGFR3 expression was found in their tumor tissues. In human ovarian carcinoma xenograft models, high levels of soluble VEGFC in ascites and serum were detected, in association with disease progression, tumor burden, and volume of ascites. Peak VEGFC expression preceded para-aortic lymph node infiltration by HOC8 neoplastic cells. Histological detection of tumor cells in blood and lymphatic vessels indicated both hematogenous and lymphatic dissemination. Overexpression of VEGFC in the VEGFR3-positive and luciferase-expressing IGROV1 cells promoted carcinoma dissemination after orthotopic transplantation in the ovary of immunodeficient mice. In vitro, VEGFC released by the tumor cells stimulated tumor cell migration in an autocrine manner. Cediranib, an inhibitor of VEGFR1-3 and c-kit, inhibited in vivo metastasis of VEGFC-overexpressing IGROV1 and in vitro autocrine effects. These findings suggest that the VEGFC/VEGFR3 pathway acts as an enhancer of ovarian cancer progression through autocrine and paracrine mechanisms, hence offering a potential target for therapy.
authors: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS; the Foundation of the Carlo Besta Neurological Institute), Bergamo and Milan, Italy.
authors: Alessandra
authors: A
authors: Decio
authors: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS; the Foundation of the Carlo Besta Neurological Institute), Bergamo and Milan, Italy.
authors: Giulia
authors: G
authors: Taraboletti
authors: Nerviano Medical Sciences Oncology, Nerviano, Italy.
authors: Veronica
authors: V
authors: Patton
authors: Nerviano Medical Sciences Oncology, Nerviano, Italy.
authors: Rachele
authors: R
authors: Alzani
authors: Department of Pathology, San Gerardo Hospital, Monza, Italy.
authors: Patrizia
authors: P
authors: Perego
authors: Department of Obstetric and Gynecology, San Gerardo Hospital, Monza, Italy.
authors: Robert
authors: R
authors: Fruscio
authors: Department of Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors: Juliane M
authors: JM
authors: Jürgensmeier
authors: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS; the Foundation of the Carlo Besta Neurological Institute), Bergamo and Milan, Italy. Electronic address: raffaella.giavazzi@marionegri.it.
authors: Raffaella
authors: R
authors: Giavazzi
authors: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS; the Foundation of the Carlo Besta Neurological Institute), Bergamo and Milan, Italy.
authors: Dorina
authors: D
authors: Belotti
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D000077216:Carcinoma, Ovarian Epithelial; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3