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Macrophages of M1 phenotype have properties that influence lung cancer cell progression.
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
Örebro University.
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2015 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 11, p. 8715-8725Article 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. Vol. 36, no 11, p. 8715-8725
Keywords [en]
M1 macrophages; M2 macrophages; MMP; Lung cancer; uPA; uPAR
National Category
Medical Biotechnology
Research subject
Biomedical Sciences
Identifiers
URN: urn:nbn:se:kau:diva-36625DOI: 10.1007/s13277-015-3630-9ISI: 000366143100059PubMedID: 26050228OAI: oai:DiVA.org:kau-36625DiVA, id: diva2:824478
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2019-11-04Bibliographically 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. p. 80
Series
Karlstad University Studies, ISSN 1403-8099 ; 2015:36
Keywords
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: 2018-01-11Bibliographically approved

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