Oncotarget

Research Papers:

Tumor-associated macrophages and individual chemo-susceptibility are influenced by iron chelation in human slice cultures of gastric cancer

Sebastian Prill _, Jakob Rebstock, Anja Tennemann, Justus Körfer, Rasmus Sönnichsen, René Thieme, Ines Gockel, Orestis Lyros, Astrid Monecke, Christian Wittekind, Arved Weimann, Kerstin Grosser, Volker Wiechmann, Christoph Kubick, Ingo Bechmann, Florian Lordick and Sonja Kallendrusch

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Oncotarget. 2019; 10:4731-4742. https://doi.org/10.18632/oncotarget.27089

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Abstract

Sebastian Prill1,2, Jakob Rebstock1,2, Anja Tennemann2, Justus Körfer2, Rasmus Sönnichsen1,2, René Thieme3, Ines Gockel3, Orestis Lyros3, Astrid Monecke4, Christian Wittekind4, Arved Weimann5, Kerstin Grosser5, Volker Wiechmann6, Christoph Kubick6, Ingo Bechmann1, Florian Lordick2,7 and Sonja Kallendrusch1

1 Institute of Anatomy, University Medicine Leipzig, Leipzig, Germany

2 University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Leipzig, Germany

3 Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Medicine Leipzig, Leipzig, Germany

4 Institute of Pathology, University Medicine Leipzig, Leipzig, Germany

5 Department of General and Visceral Surgery, Klinikum St. Georg, Leipzig, Germany

6 Department of Pathology, Klinikum St. Georg, Leipzig, Germany

7 Department of Hematology and Medical Oncology, University Medicine Leipzig, Leipzig, Germany

Correspondence to:

Sebastian Prill,email: Sebastian.Prill@medizin.uni-leipzig.de

Keywords: tumor-associated macrophages; tumor slice cultures; deferoxamine; gastric cancer; iron

Received: February 20, 2019     Accepted: June 29, 2019     Published: July 30, 2019

ABSTRACT

Purpose: Presence of tumor-associated macrophages (TAM) and high levels of ferritin and lipocalin 2 (Lcn2) in the tumor microenvironment are associated with poor prognosis in many types of cancer. Here we investigate whether iron deprivation influences TAM phenotype and chemotherapy resistance in tumor slice cultures (TSC) of gastric cancer.

Results: TAM remained morphologically and functionally stable for four DIV. DFO treatment for 72 h decreased ferritin expression in TAM and in the tumor stroma but did not alter Lcn2 expression. TAM phenotype was altered after 72 h of cisplatin or DFO treatment compared with control conditions. Single DFO treatment and combined treatment with cytotoxic drugs significantly increased tumor cell apoptosis in TSC of gastric cancer.

Methods: TSC were manufactured by cutting tissue of gastric cancer resection specimens in 350 μm thick slices and cultivating them under standard conditions on a filter membrane, at an air-liquid interface. After 24 h ex vivo, TSC were treated with irinotecan (100 nM) or cisplatin (10 μM) alone and in combination with deferoxamine (DFO; 10 μM, 100 μM), respectively, for 72 h. After four days in vitro (DIV) the TSC were fixated with paraformaldehyde, paraffin embedded and analyzed by immunohistochemistry for apoptosis (cPARP), proliferation (Ki67), TAM (CD68, CD163), ferritin, and Lcn2 expression.

Conclusions: TAM are well preserved and can be studied in TSC of gastric cancer. Iron deprivation significantly increased tumor cell apoptosis.


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