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Cancer and Inflammation: Role of Macrophages and Monocytes
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
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 [en]
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: urn:nbn:se:kau:diva-37086ISBN: 978-91-7063-654-7 (print)OAI: oai:DiVA.org:kau-37086DiVA: diva2:840568
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
List of papers
1. Conditioned media from M1 but not M2 macrophage phenotype inhibits proliferation of thr colon cancer cell lines HT29 and CACO-2
Open this publication in new window or tab >>Conditioned media from M1 but not M2 macrophage phenotype inhibits proliferation of thr colon cancer cell lines HT29 and CACO-2
2013 (English)Conference paper, Poster (with or without abstract) (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.

National Category
Medical and Health Sciences Biomedical Laboratory Science/Technology
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-30269 (URN)
Conference
NCRI cancer conference Liverpool 3-6 november
Available from: 2013-11-26 Created: 2013-11-26 Last updated: 2017-10-31Bibliographically approved
2. Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5‑fluorouracil on the HT‑29 colon cancer cell line
Open this publication in new window or tab >>Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5‑fluorouracil on the HT‑29 colon cancer cell line
2015 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 46, no 1, 37-46 p.Article in journal (Refereed) Published
Abstract [en]

Resistance of tumor cells to chemotherapy, such as 5‑fluorouracil (5‑FU), is an obstacle for successful treatment of cancer. As a follow‑up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5‑FU cytotoxicity on the colon cancer cell lines HT‑29 and CACO‑2. HT‑29 cells, but not CACO‑2 cells, having been treated with a combination of M1 CM and 5‑FU recovered their cell growth to a much larger extent compared to cells having been treated with 5‑FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT‑29, but not CACO‑2 cells, induced cell cycle arrest in the G0/G1 and G2/M phases. 5‑FU treatment induced accumulation of cells in S‑phase in both HT‑29 and CACO‑2 cells. This accumulation of cells in S‑phase was attenuated by combined M1 CM and 5‑FU treatment in HT‑29 cells, but not in CACO‑2 cells. The mRNA expression of cell cycle regulatory proteins and 5‑FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5‑FU cytotoxicity in HT‑29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT‑29 cells treated with M1 CM, making them unlikely as mediators of reduced 5‑FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT‑29 cells, but not in CACO‑2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT‑29 and neither did it change the growth recovery after combined treatment of HT‑29 cells with M1 CM and 5‑FU. In conclusion, treatment of HT‑29 cells with M1 CM reduces the cytotoxic effect of 5‑FU and this is mediated by a M1 CM induced cell cycle arrest in the G0/G1 and G2/M phases. So far, we lack an explanation why this action is absent in the CACO‑2 cells. The current findings may be important for optimization of chemotherapy in colon cancer.

Place, publisher, year, edition, pages
Spandidos publications, 2015
National Category
Medical and Health Sciences
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-36614 (URN)10.3892/ijo.2014.2696 (DOI)000345885900004 ()25310018 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2017-10-31Bibliographically approved
3. Macrophages of M1 phenotype have properties that influence lung cancer cell progression.
Open this publication in new window or tab >>Macrophages of M1 phenotype have properties that influence lung cancer cell progression.
Show others...
2015 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 11, 8715-8725 p.Article in journal (Refereed) Published
Abstract [en]

Stromal macrophages of different phenotypes can contribute to the expression of proteins that affects metastasis such as urokinase-type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), but knowledge of how essential their contribution is in comparison to the cancer cells in small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) is lacking. The expression of uPA, uPAR, and PAI-1 and of the matrix metalloproteinases (MMP)-2 and MMP-9 were studied in human macrophages of M1 and M2 phenotype and compared to a lung SCC (NCI-H520) and a SCLC (NCI-H69) cell line. Effects of treatment with conditioned media (CM) from M1 and M2 macrophages on the expression of these genes in H520 and H69 cells as well as effects on the cell growth were investigated. In addition, data on the stromal macrophages immunoreactivity of uPAR, MMP-2, and MMP-9 in a few SCC and SCLC biopsies was included. uPAR, MMP-2, and MMP-9 were confirmed in stromal cells including macrophages in the SCC and SCLC biopsies. In vitro, both macrophage phenotypes expressed considerably higher mRNA levels of uPA, uPAR, PAI-1, and MMP-9 compared to the cancer cell lines, and regarding uPAR, the highest level was found in the M1 macrophage phenotype. Furthermore, M1 CM treatment not only induced an upregulation of PAI-1 in both H520 and H69 cells but also inhibited cell growth in both cell lines, giving M1 macrophages both tumor-promoting and tumor-killing potential.

Place, publisher, year, edition, pages
Springer, 2015
Keyword
M1 macrophages; M2 macrophages; MMP; Lung cancer; uPA; uPAR
National Category
Medical Biotechnology
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-36625 (URN)10.1007/s13277-015-3630-9 (DOI)000366143100059 ()26050228 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2017-10-31Bibliographically approved
4. Green, black and rooibos tea inhibit prostaglandin E2 formation in human monocytes by inhibiting expression of enzymes in the prostaglandin E2 pathway
Open this publication in new window or tab >>Green, black and rooibos tea inhibit prostaglandin E2 formation in human monocytes by inhibiting expression of enzymes in the prostaglandin E2 pathway
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
green tea, black tea, rooibos tea, monocytes, microsomal prostaglandin E2 synthase, cyclooxygenase, prostaglandin E2, phospholipase A2
National Category
Cell Biology Immunology Nutrition and Dietetics
Identifiers
urn:nbn:se:kau:diva-37085 (URN)
Available from: 2015-07-06 Created: 2015-07-06 Last updated: 2015-10-02Bibliographically approved

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