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

Summary, in English

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.

• Författare: Kishan Bellamkonda; Naveen Kumar Chandrashekar; Janina Osman; Benson Chellakkan Selvanesan; Sayeh Savari; Anita Sjölander
• Avdelning/ar: Institutionen för translationell medicin; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
• Publiceringsår: 2016-07-07
• Språk: Engelska
• Publikation/Tidskrift/Serie: BMC Cancer
• Volym: 16
• Issue: 1
• Länkar: http://dx.doi.org/10.1186/s12885-016-2466-z
• Dokumenttyp: Artikel i tidskrift
• Förlag: BioMed Central (BMC)
• Ämne: Cancer and Oncology
• Nyckelord: ALDH; Cancer-initiating cells; Colon cancer; Inflammation; LTD; PGE
• Status: Published
• ISBN/ISSN/Övrigt: ISSN: 1471-2407