The Role of Inflammatory Lipid Mediators on Colon Cancer Initiating Cells (CICs)
type: CreativeWork
description: 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 i…
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 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 i…
author: Bellamkonda, Kishan
language: eng
keywords: Clinical Medicine
date published: 2015
date modified: 2026-07-24T02:59:36Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Laboratory Medicine, Lund University