title: Impaired lymphatic function accelerates cancer growth.
abstract: Increased lymphangiogenesis is a common feature of cancer development and progression, yet the influence of impaired lymphangiogenesis on tumor growth is elusive. C3HBA breast cancer and KHT-1 sarcoma cell lines were implanted orthotopically in Chy mice, harboring a heterozygous inactivating mutation of vascular endothelial growth factor receptor-3, resulting in impaired dermal lymphangiogenesis. Accelerated tumor growth was observed in both cancer models in Chy mice, coinciding with reduced peritumoral lymphangiogenesis. An impaired lymphatic washout was observed from the peritumoral area in Chy mice with C3HBA tumors, and the number of macrophages was significantly reduced. While fewer macrophages were detected, the fraction of CD163+ M2 macrophages remained constant, causing a shift towards a higher M2/M1 ratio in Chy mice. No difference in adaptive immune cells was observed between wt and Chy mice. Interestingly, levels of pro- and anti-inflammatory macrophage-associated cytokines were reduced in C3HBA tumors, pointing to an impaired innate immune response. However, IL-6 was profoundly elevated in the C3HBA tumor interstitial fluid, and treatment with the anti-IL-6 receptor antibody tocilizumab inhibited breast cancer growth. Collectively, our data indicate that impaired lymphangiogenesis weakens anti-tumor immunity and favors tumor growth at an early stage of cancer development.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Eli Sihn Samdal
authors.initials: ES
authors.lastname: Steinskog
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Solfrid Johanne
authors.initials: SJ
authors.lastname: Sagstad
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Marek
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Tine Veronica
authors.initials: TV
authors.lastname: Karlsen
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Carl Erik
authors.initials: CE
authors.lastname: Markhus
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Synnøve
authors.initials: S
authors.lastname: Yndestad
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Wiig
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Hans Petter
authors.initials: HP
authors.lastname: Eikesdal
mesh_terms: D000818:Animals; D015850:Interleukin-6 / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
chemical_list: D015850:Interleukin-6; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Chy mice; IL-6; cancer; lymphangiogenesis; tumor associated macrophages