The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model
| Autor: | Kishan Bellamkonda, Naveen Kumar Chandrashekar, Anita Sjölander, Janina Osman, Benson Chellakkan Selvanesan, Sayeh Savari |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer medicine.medical_treatment Leukotriene D4 Mice 0302 clinical medicine Nude mouse Doublecortin-Like Kinases Tumor Microenvironment Medicine biology Intracellular Signaling Peptides and Proteins respiratory system Colon cancer CXCL1 Cytokine Oncology 030220 oncology & carcinogenesis Colonic Neoplasms Neoplastic Stem Cells Cytokines lipids (amino acids peptides and proteins) Female PGE2 medicine.symptom Cancer-initiating cells Prostaglandin E Research Article ALDH Mice Nude Inflammation Protein Serine-Threonine Kinases Dinoprostone 03 medical and health sciences Immune system Genetics Animals Humans Tumor microenvironment business.industry Neoplasms Experimental medicine.disease biology.organism_classification HCT116 Cells 030104 developmental biology LTD4 Immunology Cancer research business |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2466-z) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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