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The Role of Inflammatory Lipid Mediators on Colon Cancer Initiating Cells (CICs)

Bellamkonda, Kishan LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:18.
Abstract
Colorectal cancer (CRC) is one of the major causes of cancer globally. Recent studies proposed a role for cancer initiating cells (CICs), a small subset of replication-competent cells, in colon carcinogenesis. Although the role of inflammatory lipid-mediators in CRC progression is well known, their role in the promotion of cancer-initiating cells remains to be elucidated. For this thesis, we investigated the role of eicosanoids – leukotriene D4 (LTD4) or prostaglandin E2 (PGE2) – on CIC properties and changes occurring in the tumor environment that could possibly support CIC-induced tumor growth. To this end, we identified the CICs on the basis of ALDH expression and evaluated their in vitro characteristics like colony formation, radio or... (More)
Colorectal cancer (CRC) is one of the major causes of cancer globally. Recent studies proposed a role for cancer initiating cells (CICs), a small subset of replication-competent cells, in colon carcinogenesis. Although the role of inflammatory lipid-mediators in CRC progression is well known, their role in the promotion of cancer-initiating cells remains to be elucidated. For this thesis, we investigated the role of eicosanoids – leukotriene D4 (LTD4) or prostaglandin E2 (PGE2) – on CIC properties and changes occurring in the tumor environment that could possibly support CIC-induced tumor growth. To this end, we identified the CICs on the basis of ALDH expression and evaluated their in vitro characteristics like colony formation, radio or chemoresistance and in vivo tumorigenic properties in the presence of LTD4 or PGE2. We showed that LTD4 and PGE2 enriched the ALDH+ cell population

and augmented the colonies formation and tumor progression in xenograft mice model. The ALDH+ cells were also resistant to 5-fluorouracil and radiation that is additionally augmented by both the lipid-mediators. Moreover

the impact of lipid inflammatory mediators on the stemness properties of CICs was evident by increased expression of genes that confer survival and self-renewal ability to CICs. In immunodeficient mice, LTD4 or PGE2

treatment amplified CIC-induced tumor growth. Furthermore, LTD4 and PGE2 increased cell proliferation activated β-catenin signaling and up-regulated COX-2. Additionally, LTD4 or PGE2 drive massive inflammatory responses identified as CD45+ enrichment, particularly of macrophages within tumors. The ability of ALDH+ cells to form tumors in immunodeficient mice could not be challenged by radiation therapy.



In a separate series of experiments, we investigated the contribution of CICs in the development of sensitivity against montelukast, a CysLT1R antagonist. In this context we report that sensitivity of tumors against

montelukast could depend on the variation in CICs content, activation of prosurvival factors such as BCL-2 and β-catenin signaling. Collectively, our data showed that LTD4 and PGE2 exacerbate CIC characteristics and promote

tumor growth by allowing modifications in the tumor environment. New therapeutic strategies could aim to resolve not only cancer associated inflammation, but also to target CICs in order to achieve better remission and cure advanced colon cancer stages. (Less)
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author
supervisor
opponent
  • Dr. Holmberg, Johan, Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:18
pages
60 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Auditoriet, plan 3, Jan Waldenströms gata 47, Skånes Universitetssjukhus, Malmö.
defense date
2015-01-16 09:00
ISSN
1652-8220
ISBN
978-91-7619-071-5
language
English
LU publication?
yes
id
0508131a-f493-4934-b5ea-5b2460767f5b (old id 4927666)
date added to LUP
2015-01-14 09:34:36
date last changed
2016-09-19 08:44:45
@phdthesis{0508131a-f493-4934-b5ea-5b2460767f5b,
  abstract     = {Colorectal cancer (CRC) is one of the major causes of cancer globally. Recent studies proposed a role for cancer initiating cells (CICs), a small subset of replication-competent cells, in colon carcinogenesis. Although the role of inflammatory lipid-mediators in CRC progression is well known, their role in the promotion of cancer-initiating cells remains to be elucidated. For this thesis, we investigated the role of eicosanoids – leukotriene D4 (LTD4) or prostaglandin E2 (PGE2) – on CIC properties and changes occurring in the tumor environment that could possibly support CIC-induced tumor growth. To this end, we identified the CICs on the basis of ALDH expression and evaluated their in vitro characteristics like colony formation, radio or chemoresistance and in vivo tumorigenic properties in the presence of LTD4 or PGE2. We showed that LTD4 and PGE2 enriched the ALDH+ cell population<br/><br>
and augmented the colonies formation and tumor progression in xenograft mice model. The ALDH+ cells were also resistant to 5-fluorouracil and radiation that is additionally augmented by both the lipid-mediators. Moreover<br/><br>
the impact of lipid inflammatory mediators on the stemness properties of CICs was evident by increased expression of genes that confer survival and self-renewal ability to CICs. In immunodeficient mice, LTD4 or PGE2<br/><br>
treatment amplified CIC-induced tumor growth. Furthermore, LTD4 and PGE2 increased cell proliferation activated β-catenin signaling and up-regulated COX-2. Additionally, LTD4 or PGE2 drive massive inflammatory responses identified as CD45+ enrichment, particularly of macrophages within tumors. The ability of ALDH+ cells to form tumors in immunodeficient mice could not be challenged by radiation therapy.<br/><br>
<br/><br>
In a separate series of experiments, we investigated the contribution of CICs in the development of sensitivity against montelukast, a CysLT1R antagonist. In this context we report that sensitivity of tumors against<br/><br>
montelukast could depend on the variation in CICs content, activation of prosurvival factors such as BCL-2 and β-catenin signaling. Collectively, our data showed that LTD4 and PGE2 exacerbate CIC characteristics and promote<br/><br>
tumor growth by allowing modifications in the tumor environment. New therapeutic strategies could aim to resolve not only cancer associated inflammation, but also to target CICs in order to achieve better remission and cure advanced colon cancer stages.},
  author       = {Bellamkonda, Kishan},
  isbn         = {978-91-7619-071-5},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {60},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {The Role of Inflammatory Lipid Mediators on Colon Cancer Initiating Cells (CICs)},
  volume       = {2015:18},
  year         = {2015},
}