title: The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model.
abstract: Colorectal cancer is one of the most common types of cancers worldwide. Recent studies have identified cancer-initiating cells (CICs) as a subgroup of replication-competent cells in the development of colorectal cancer. Although it is understood that an inflammation-rich tumor microenvironment presumably supports CIC functions, the contributory factors are not very well defined. The present study advances our understanding of the role of the eicosanoids leukotriene D4 (LTD4) and prostaglandin E2 (PGE2) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth.
  
  
  
  In this study we used human HCT-116 colon cancer ALDH(+) cells in a nude mouse xenograft model. Protein expression and immune cell was determined in tumor-dispersed cells by flow cytometry and in tumor sections by immunohistochemistry. mRNA expressions were quantified using RT-q-PCR and plasma cytokine levels by Multiplex ELISA.
  
  
  
  We observed that LTD4 and PGE2 treatment augmented CIC-induced tumor growth. LTD4-and PGE2-treated xenograft tumors revealed a robust increase in ALDH and Dclk1 protein expression, coupled with activated β-catenin signaling and COX-2 up-regulation. Furthermore, LTD4 or PGE2 accentuated the accumulation of CD45 expressing cells within xenograft tumors. Further analysis revealed that these infiltrating immune cells consisted of neutrophils (LY6G) and M2 type macrophages (CD206(+)). In addition, LTD4 and PGE2 treatment significantly elevated the plasma levels of cysteinyl leukotrienes and PGE2, as well as levels of IL-1β, IL-2, IL-6, TNF-α and CXCL1/KC/GRO. In addition, increased mRNA expression of IL-1β, IL-6 and IL-10 were detected in tumors from mice that had been treated with LTD4 or PGE2.
  
  
  
  Our data suggest that both LTD4 and PGE2 promote CICs in initiating tumor growth by allowing modifications in the tumor environment. Our data indicate that new therapeutic strategies targeting eicosanoids, specifically LTD4 and PGE2, could be tested for better therapeutic management of colon cancer.
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
authors.forename: Kishan
authors.initials: K
authors.lastname: Bellamkonda
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
authors.forename: Naveen Kumar
authors.initials: NK
authors.lastname: Chandrashekar
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
authors.forename: Janina
authors.initials: J
authors.lastname: Osman
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
authors.forename: Benson Chellakkan
authors.initials: BC
authors.lastname: Selvanesan
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden.
authors.forename: Sayeh
authors.initials: S
authors.lastname: Savari
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, SE-205 02, Malmö, Sweden. anita.sjolander@med.lu.se.
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000633:toxicity*; D000089742:Doublecortin-Like Kinases; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D017998:Leukotriene D4 / Q000633:toxicity*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D017998:Leukotriene D4; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone
keywords: ALDH; Cancer-initiating cells; Colon cancer; Inflammation; LTD4; PGE2