Oncotarget

Research Papers:

Impaired lymphatic function accelerates cancer growth

Eli Sihn Samdal Steinskog _, Solfrid Johanne Sagstad, Marek Wagner, Tine Veronica Karlsen, Ning Yang, Carl Erik Markhus, Synnøve Yndestad, Helge Wiig and Hans Petter Eikesdal

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Oncotarget. 2016; 7:45789-45802. https://doi.org/10.18632/oncotarget.9953

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Abstract

Eli Sihn Samdal Steinskog1, Solfrid Johanne Sagstad1, Marek Wagner1, Tine Veronica Karlsen1, Ning Yang1, Carl Erik Markhus1, Synnøve Yndestad2,3, Helge Wiig1, Hans Petter Eikesdal2,3

1Department of Biomedicine, University of Bergen, Bergen, Norway

2Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

3Department of Oncology, Haukeland University Hospital, Bergen, Norway

Correspondence to:

Hans Petter Eikesdal, email: hans.eikesdal@k2.uib.no

Keywords: cancer, lymphangiogenesis, Chy mice, tumor associated macrophages, IL-6

Received: January 05, 2016    Accepted: May 22, 2016    Published: June 13, 2016

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.


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