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The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model

Bellamkonda, Kishan LU ; Chandrashekar, Naveen Kumar; Osman, Janina LU ; Selvanesan, Benson Chellakkan LU ; Savari, Sayeh LU and Sjölander, Anita LU (2016) In BMC Cancer 16(1).
Abstract

Background: 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. Methods: In this study we used human... (More)

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ALDH, Cancer-initiating cells, Colon cancer, Inflammation, LTD, PGE
in
BMC Cancer
volume
16
issue
1
publisher
BioMed Central
external identifiers
  • Scopus:84978811128
ISSN
1471-2407
DOI
10.1186/s12885-016-2466-z
language
English
LU publication?
yes
id
62a3dad8-ce2a-4ee9-ad6f-150b8bf63b1a
date added to LUP
2016-08-16 16:46:36
date last changed
2016-08-16 16:49:03
@misc{62a3dad8-ce2a-4ee9-ad6f-150b8bf63b1a,
  abstract     = {<p>Background: 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 D<sub>4</sub> (LTD<sub>4</sub>) and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth. Methods: In this study we used human HCT-116 colon cancer ALDH<sup>+</sup> 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. Results: We observed that LTD<sub>4</sub> and PGE<sub>2</sub> treatment augmented CIC-induced tumor growth. LTD<sub>4</sub>-and PGE<sub>2</sub>-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, LTD<sub>4</sub> or PGE<sub>2</sub> 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<sup>+</sup>). In addition, LTD<sub>4</sub> and PGE<sub>2</sub> treatment significantly elevated the plasma levels of cysteinyl leukotrienes and PGE<sub>2</sub>, 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 LTD<sub>4</sub> or PGE<sub>2</sub>. Conclusion: Our data suggest that both LTD<sub>4</sub> and PGE<sub>2</sub> promote CICs in initiating tumor growth by allowing modifications in the tumor environment. Our data indicate that new therapeutic strategies targeting eicosanoids, specifically LTD<sub>4</sub> and PGE<sub>2</sub>, could be tested for better therapeutic management of colon cancer.</p>},
  author       = {Bellamkonda, Kishan and Chandrashekar, Naveen Kumar and Osman, Janina and Selvanesan, Benson Chellakkan and Savari, Sayeh and Sjölander, Anita},
  issn         = {1471-2407},
  keyword      = {ALDH,Cancer-initiating cells,Colon cancer,Inflammation,LTD,PGE},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {ARRAY(0x9535ec8)},
  series       = {BMC Cancer},
  title        = {The eicosanoids leukotriene D<sub>4</sub> and prostaglandin E<sub>2</sub> promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model},
  url          = {http://dx.doi.org/10.1186/s12885-016-2466-z},
  volume       = {16},
  year         = {2016},
}