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Cited by 454

The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.

The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer

Edin, Sofia, Wikberg, Maria L., Dahlin, Anna M., Rutegård, Jörgen, Öberg, Åke, Oldenborg, Per-Arne, Palmqvist, Richard·2012·PLoS ONE
DOI 10.1371/journal.pone.0047045PMC PMC3471949
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Abstract

High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2(+)) or M2 (CD163(+)) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2(+) and CD163(+) cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2(+) cells had a significantly better prognosis than those infiltrated by few NOS2(+) cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.

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Figures

Figure 1 NOS2 and CD163 distinguish between different macrophage phenotypes. Confocal images of immunoflourescent stainings in CRC of (A) NOS2 (red) and CD163 (green), (B) CD68 (red) and CD163 (green) and (C) NOS2 (red) and CD68 (green). Nuclei are revealed by DAPI staining (blue), and overlay is flourescense collected by all channels.
Figure 1 NOS2 and CD163 distinguish between different macrophage phenotypes. Confocal images of immunoflourescent stainings in CRC of (A) NOS2 (red) and CD163 (green), (B) CD68 (red) and CD163 (green) and (C) NOS2 (red) and CD68 (green). Nuclei are revealed by DAPI staining (blue), and overlay is flourescense collected by all channels.CC BY · PubMed Central
Figure 2 NOS2 and CD163 immunoreactivity in patient samples. Representative light microscopic images of immunohistochemical stainings of NOS2 and CD163 in consecutive sections of the same CRC tumor sample.
Figure 2 NOS2 and CD163 immunoreactivity in patient samples. Representative light microscopic images of immunohistochemical stainings of NOS2 and CD163 in consecutive sections of the same CRC tumor sample.CC BY · PubMed Central
Figure 3 Cancer-specific survival in CRC patients. CRC cases were scored for NOS2 (A–C) and CD163 (D–F) expression, score 1–4. Shown are Kaplan-Meier plots of cancer-specific survival in (A and D) all CRCs, (B and E) potentially curatively resected colon cancers, and (C and F) potentially curatively resected rectal cancers. Log-rank tests were used to calculate P values.
Figure 3 Cancer-specific survival in CRC patients. CRC cases were scored for NOS2 (A–C) and CD163 (D–F) expression, score 1–4. Shown are Kaplan-Meier plots of cancer-specific survival in (A and D) all CRCs, (B and E) potentially curatively resected colon cancers, and (C and F) potentially curatively resected rectal cancers. Log-rank tests were used to calculate P values.CC BY · PubMed Central
Figure 4 NOS2/CD163 ratios and cancer-specific survival in CRC. Cancer-specific survival of CRC cases scored for the NOS2/CD163 ratio. Shown are Kaplan-Meier plots of the NOS2/CD163 ratio in (A) all CRCs, or (B) potentially curatively resected colon cancers. Log-rank tests were used to calculate P values.
Figure 4 NOS2/CD163 ratios and cancer-specific survival in CRC. Cancer-specific survival of CRC cases scored for the NOS2/CD163 ratio. Shown are Kaplan-Meier plots of the NOS2/CD163 ratio in (A) all CRCs, or (B) potentially curatively resected colon cancers. Log-rank tests were used to calculate P values.CC BY · PubMed Central
Figure 5 Cancer-specific survival in subgroups of CRC arranged according to MSI screening status. Subgroups of CRC were arranged according to MSI screening status and scored for NOS2 (A–C) and CD163 (D–F) expression, score 1–4. Shown are Kaplan-Meier plots of cancer-specific survival in (A and D) MSI cases, (B and E) MSS cases, and (C and F) combined MSI screening status and NOS2 or CD163, score 1–2 or 3–4, respectively. Log-rank tests were used to calculate P values.
Figure 5 Cancer-specific survival in subgroups of CRC arranged according to MSI screening status. Subgroups of CRC were arranged according to MSI screening status and scored for NOS2 (A–C) and CD163 (D–F) expression, score 1–4. Shown are Kaplan-Meier plots of cancer-specific survival in (A and D) MSI cases, (B and E) MSS cases, and (C and F) combined MSI screening status and NOS2 or CD163, score 1–2 or 3–4, respectively. Log-rank tests were used to calculate P values.CC BY · PubMed Central
Figure 6 Cancer-specific survival in subgroups of CRC arranged according to CIMP status. Subgroups of CRC were arranged according to CIMP status and scored for NOS2 (A–D) and CD163 (E–H) expression, score 1–4. Shown are Kaplan-Meier plots of specimens of (A and E) CIMP-negative cases, (B and F) CIMP-low cases, (C and G) CIMP-high cases, and (D and H) combined CIMP status and NOS2 or CD163, score 1–2 or 3–4, respectively. Log-rank tests were used to calculate P values.
Figure 6 Cancer-specific survival in subgroups of CRC arranged according to CIMP status. Subgroups of CRC were arranged according to CIMP status and scored for NOS2 (A–D) and CD163 (E–H) expression, score 1–4. Shown are Kaplan-Meier plots of specimens of (A and E) CIMP-negative cases, (B and F) CIMP-low cases, (C and G) CIMP-high cases, and (D and H) combined CIMP status and NOS2 or CD163, score 1–2 or 3–4, respectively. Log-rank tests were used to calculate P values.CC BY · PubMed Central

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Metadata

Authors
Edin, S., Wikberg, M. L., Dahlin, A. M., Rutegård, J., Öberg, Å., Oldenborg, P.-A., & Palmqvist, R.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-10-15
Volume
7
Issue
10
Pages
e47045
ISSN
1932-6203
DOI
10.1371/journal.pone.0047045
PMC
PMC3471949
Cited by
454
References
65
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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CoChat. (2026). Citation check: The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer. https://app.cochat.ai/papers/10.1371/journal.pone.0047045
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Edin, S., Wikberg, M. L., Dahlin, A. M., Rutegård, J., Öberg, Å., Oldenborg, P.-A., & Palmqvist, R. (2012). The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer. PLoS ONE. https://doi.org/10.1371/journal.pone.0047045

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