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Conditioned media from M1 but not M2 macrophage phenotype inhibits proliferation of thr colon cancer cell lines HT29 and CACO-2
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
Örebro universitet.
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
2013 (English)Conference paper, Poster (Refereed)
Abstract [en]

Background

Tumor associated macrophages (TAMs) are often present at a high level in colorectal cancer (CRC) but whether the presence of TAMs in CRC is good or bad is unclear. Macrophages can be categorized into two main subgroups, M1 or M2, that display pro – and anti-inflammatory properties respectively. An improved knowledge of the different macrophage phenotypes will broaden the understanding of their involvement in CRC. We have used an in vitro model to study the effects of human M1 and M2 macrophages on the growth and cell cycle of colon cancer cell lines.

 

Method

Human monocytes were differentiated into M1 or M2 macrophages and conditioned media was collected. Effects of the conditioned media were measured on the colon cancer cell lines HT-29 and CACO-2 in regards to proliferation, cell cycle distribution and apoptosis. A protein array was used to analyze the released amount of 42 different cytokines from M1 and M2 macrophages into the collected conditioned media.

 

Results

Growth arrest was induced in HT-29 and CACO-2 by M1 conditioned media, while M2 conditioned media had no major effect. Analysis of cell cycle distribution and apoptosis in HT-29 cells revealed that treatment with M1 conditioned media on these cells increased apoptosis and caused a disturbed cell cycle with accumulation in G0/G1 and G2/M and a corresponding reduction in S-phase. The protein array revealed several cytokines expressed in M1 with potential inhibitory growth effects. We treated HT-29 cells with two of the candidates, TNF-a and CXCL9, but neither induced growth arrest.

 

Conclusion

M1 – but not M2-macrophages had a major inhibitory effect on the growth of the colon cancer cell lines HT-29 and CACO-2 and suggest a role for M1 macrophages in anti-tumor activity and possible favorable outcome for CRC patients.

Place, publisher, year, edition, pages
2013.
National Category
Medical and Health Sciences Biomedical Laboratory Science/Technology
Research subject
Biomedical Sciences
Identifiers
URN: urn:nbn:se:kau:diva-30269OAI: oai:DiVA.org:kau-30269DiVA: diva2:667400
Conference
NCRI cancer conference Liverpool 3-6 november
Available from: 2013-11-26 Created: 2013-11-26 Last updated: 2015-08-17Bibliographically approved
In thesis
1. Cancer and Inflammation: Role of Macrophages and Monocytes
Open this publication in new window or tab >>Cancer and Inflammation: Role of Macrophages and Monocytes
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Macrophages are cells of the innate immune system that can be found in large quantities in cancer tumors and affect cancer progression by regulating growth and invasiveness of cancer cells. There are two main phenotypes of macrophages denoted M1 and M2. In this thesis, the M1 and M2 phenotype of human macrophages were characterized, and effects of the macrophages on the growth and invasiveness of colon and lung cancer cells were studied.

Macrophages of the M1 phenotype, but not the M2 phenotype, inhibited growth of both colon and lung cancer cells, and the inhibition for some of the cancer cell lines was induced by cell cycle arrest in the G1/G0 and/or G2/M cell cycle phases. In the colon cancer cell line, the macrophage induced cell cycle arrest was found to attenuate the cytotoxic effect of the chemotherapeutic drug 5-FU. Macrophages were also shown to express high levels of proteases (matrix metalloproteinase-2 and 9) and high levels of proteins of the urokinase-type plasminogen activator (uPA) system, in comparison to the lung cancer cell lines studied. Expression of these has been found to predict poor outcome in lung cancer, and the results suggest macrophages to be important contributors of these in lung tumors. Furthermore, the M1 phenotype was found to express higher levels of the uPA receptor than the M2 phenotype.

Prostaglandin E2 (PGE2) is a potent inflammatory molecule expressed by e.g. macrophages and monocytes, and inhibition of its expression has been shown to reduce the risk of colon cancer. Green tea and black tea was found to be potent inhibitors of PGE2 formation in human monocytes, and the inhibitory effects of green tea was likely due to its content of the polyphenol epigallocatechin gallate. Rooibos tea also inhibited PGE2 formation, but was less potent than green and black tea. The primary mechanism for the inhibition was via inhibition of expression of enzymes in the PGE2 formation pathway, and primarily microsomal prostaglandin synthase-1.

Abstract [en]

Macrophages are cells of the immune system often found in large numbers in cancer tumors. They affect multiple aspects of cancer progression, including growth and spread of cancer cells, and the efficacy of treatments. There are two major macrophage phenotypes denoted M1 and M2, that have mainly pro- and anti-inflammatory properties, respectively.

In this thesis, M1 and M2 macrophages were characterized and effects of them on different aspects of cancer progression were studied using culture of colon, and lung cancer cells.

The M1 phenotype inhibited proliferation of cancer cells from both colon and lung. The growth inhibition was for some cell lines accompanied by cell cycle arrest.

The macrophage induced cell cycle arrest was found to protect colon cancer cells from the cytostatic drug 5-fluorouracil.

Prostaglandin E2 (PGE2) contributes to colon cancer development and treatment of monocytes with tea extracts inhibited PGE2 formation via inhibition of expression of microsomal prostaglandin E synthase-1.

Proteases can degrade the extracellular matrix of a tumor to facilitate cancer cell invasion and metastasis. The M1 and M2 phenotypes of macrophages expressed several protease activity related genes to a greater extent than lung cancer cells, and M1 more so than the M2 phenotype.

Place, publisher, year, edition, pages
Karlstad: Karlstads universitet, 2015. 80 p.
Series
Karlstad University Studies, ISSN 1403-8099 ; 2015:36
Keyword
M1 macrophages, M2 macrophages, colon cancer, lung cancer, prostaglandin E2
National Category
Immunology Cell and Molecular Biology Cancer and Oncology
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-37086 (URN)978-91-7063-654-7 (ISBN)
Public defence
2015-08-31, Nyquistsalen, 9C203, Karlstads universitet 651 88 Karlstad, Karlstad, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2015-08-17 Created: 2015-07-06 Last updated: 2015-08-17Bibliographically approved

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Engström, AlexanderErlandsson, AnnWijkander, Jonny
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