Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

Shabo, Ivan; Olsson, Hans; Elkarim, Rihab; Sun, Xiao‐Feng; Svanvik, Joar

doi:10.1007/s12307-014-0145-7

Cited by 35 publications

(40 citation statements)

References 57 publications

(72 reference statements)

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“…Apart from CD163, several other TAM markers such as IL-10, iNOS, and VEGF have been used for diagnosis of tumor staging in lung, 38 breast, 39 and colon cancers. 40 The upregulation of CD163, VEGF, and IL-10 and the downregulation of iNOS in LMNCs indicates the presence of M2-like TAMs in our experimental model. Several reports indicate that TAMs perform multiple M2-associated functions including promotion of angiogenesis, matrix remodeling, and suppression of adaptive immunity.…”

Section: Discussionmentioning

confidence: 61%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFa (M1) and CD163/ CD206 (M2) expression using flow cytometry. Role of hif-1a-induced IL-10 was dissected in hepatocyte specific hif-1aKO and hif-1adPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN C HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/ 80 C CD11b C ) infiltration to liver and DEN C HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1a, and livers from hif-1a over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1a and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1a in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1a mediated IL-10 polarizing M2 macrophages.

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Section: Discussionmentioning

confidence: 61%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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“…Clinical observations have shown that high macrophage infiltration is generally associated with poor prognosis in human cancer, including breast, gastric, prostatic, pancreatic, ovarian, and cervical carcinomas (12)(13)(14)(15)(16). Interestingly, contradictory results have also been reported in several types of human cancers, including colorectal cancer (17)(18)(19)(20)(21)(22). In colorectal cancer, an increased infiltration of TAMs was associated with lymph node metastases and tumor progression (19,21), and M2 macrophage infiltration was associated with poor prognosis in colorectal cancer (20,22).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, contradictory results have also been reported in several types of human cancers, including colorectal cancer (17)(18)(19)(20)(21)(22). In colorectal cancer, an increased infiltration of TAMs was associated with lymph node metastases and tumor progression (19,21), and M2 macrophage infiltration was associated with poor prognosis in colorectal cancer (20,22). However, increased macrophage infiltration was also reported to correlate with improved survival in colorectal cancer (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…These reports suggest that immune cells, especially macrophages in TME, may play key roles in modulating biological phenotypes of cancer cells. In colorectal cancer, contradictory conclusions about the effects of TAMs on patient prognosis have been reported (17)(18)(19)(20)(21)(22), and the detailed roles of TAMs in colorectal cancer chemoresistance are largely unclear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6

Yin

Yao

et al. 2017

Clinical Cancer Research

213

169

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Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the functions, mechanisms, and clinical significance of TAMs in colorectal cancer. We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both and models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism. TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells. Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment. .

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“…The presence of CD163 + macrophages was suggested to have a stronger association with less favorable clinicopathological features than CD68 + macrophages (Medrek, Ponten, Jirstrom, & Leandersson, 2012). Numerous studies demonstrate that elevated CD163 expression correlates with advanced cancer stages, unfavorable prognosis, early distant recurrence, and reduced patient survival in various types of cancer, which include melanoma (Jensen et al, 2009), meningioma (Kanno et al, 2013), breast cancer (Mansfield, Heikkila, von Smitten, Vakkila, & Leidenius, 2012; Shabo, Stal, Olsson, Dore, & Svanvik, 2008; Tiainen et al, 2014), colorectal cancer (Edin et al, 2012; Shabo, Olsson, Elkarim, Sun, & Svanvik, 2014), oral squamous cell carcinoma (He, Bao, et al, 2014; Wang et al, 2014), ovarian carcinoma (Reinartz et al, 2014), HCC (Kong et al, 2013), angiosarcoma (Fujimura et al, 2013), glioma (Komohara et al, 2008), and gastrointestinal stromal tumors (van Dongen et al, 2010), and hematopoietic malignancies, such as T cell leukemia/lymphoma (Komohara et al, 2013), acute myeloid leukemia (Garcia, Gardner, & Reichard, 2008), and classical Hodgkin lymphoma (Klein et al, 2014; Koh, Park, Yoon, Suh, & Huh, 2014). A recent study showed that relapse of head and neck cancer after chemoradiotherapy also correlated with CD163 + macrophages in primary tumor and CD11b + myeloid cells in recurrences (Balermpas et al, 2014).…”

Section: Scavenger Receptors In Cancer Immunobiologymentioning

confidence: 99%

Scavenger Receptors

Guo

Fisher

et al. 2015

Advances in Cancer Research

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Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted.

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Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

Cited by 35 publications

References 57 publications

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6

Scavenger Receptors

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