Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles

Cortés, Marlies; Sanchez‐Moral, Lidia; Barrios, Oriol de; Fernández-Aceñero, M. Jesús; Martínez‐Campanario, MC; Esteve‐Codina, Anna; Darling, Douglas S.; Győrffy, Balázs; Lawrence, Toby; Dean, Douglas C.; Postigo, Antonio

doi:10.15252/embj.201797345

Cited by 118 publications

(104 citation statements)

References 65 publications

(162 reference statements)

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“…Numerous studies had shown that high CD163 + TAM subtype infiltration was significantly associated with poor clinical outcomes in numerous solid tumors (8,37,38). Cortes et al revealed that ZEB1 + TAM subtype was correlated with tumor growth, chemotherapy resistance and poor survival in ovarian carcinoma (39). In this work, we confirmed that Wnt5a + TAM subtype was a preferable indicator of CRC prognosis to TAM.…”

Section: Discussionsupporting

confidence: 81%

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

Liu

Yang

Wang

et al. 2019

Preprint

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Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood.Methods: Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a-treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a+ TAMs on CRC tumorigenesis.Results: We found that high Wnt5a+CD68+/CD68+ TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a+ TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5amediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs.Conclusions: Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway-mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.

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Section: Discussionsupporting

confidence: 81%

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

Liu

Yang

Wang

et al. 2019

Preprint

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“…2 Accumulating evidence indicates that the potential recurring and metastatic behavior of ovarian cancer is attributable to the characteristics of tumor associated macrophages (TAMs). 3,4 It is generally accepted that TAMs represent a distinct type of M2 macrophages and show mostly pro-tumoral functions, including the promotion of tumor cell proliferation, invasion, and metastasis. 5,6 Much clinical data show a close association of M2 TAMs with poor outcome for ovarian cancer patients.…”

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confidence: 99%

Cross‐talk between ovarian cancer cells and macrophages through periostin promotes macrophage recruitment

Meng

Liu

et al. 2018

Cancer Science

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Tumor‐associated macrophages (TAMs) contribute to tumor progression, but it is not clear how they are recruited to tumor sites. Here we showed that periostin (POSTN) was present at high levels in ovarian cancer ascetic fluids and was correlated with CD163+ TAMs. The high POSTN level and macrophage infiltration were inversely associated with relapse‐free survival for ovarian cancer patients. In vitro studies showed that coculture with macrophages significantly increased POSTN production in ovarian cancer cells. Further investigation found that POSTN production in ovarian cancer cells was promoted by transforming growth factor‐β generated by macrophages. Moreover, siRNA of POSTN and POSTN neutralizing antibody treatment showed that ovarian cancer cell‐derived POSTN promoted the recruitment of macrophages and modulated their cytokine secretion profile. Collectively, these data indicated that POSTN was an important factor for macrophage recruitment in the tumor microenvironment and is involved in the interactions between macrophages and ovarian cancer cells.

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“…Expression of ZEB1 in macrophages polarized them to become an F4/80 low pro-tumor phenotype and contributed to chemoresistance in mice of ovarian cancer. Elevated expression of CCR2 and MMP9 in ZEB1 wildtype F4/80 low macrophages provided a positive feedback loop with ZEB1 wildtype cancer cells through cancer cell-expressed CCL2 cytokines [53]. Meanwhile, MMP9 secreted from TAMs containing ZEB1 was shown to upregulate CCL2 expression in ovarian cancer cells.…”

Section: Activation Of Cell-stimulating Growth Factors and Cytokines mentioning

confidence: 94%

“…One of the main features of tumor cells during tumor progression is their enhanced migration, invasiveness, and angiogenesis through the epithelial-mesenchymal transition (EMT) process. Several lines of evidence have indicated that TAMs are capable of promoting EMT of tumor cells through their secreted factors, including growth factors and cytokines, such as the previously mentioned epidermal growth factor (EGF), and transforming growth factor-β (TGF-β) [52][53][54][55]. Co-culture of M2 macrophages that were polarized from THP1 monocytes with oral cancer or head and neck squamous cancer cells induced the EMT of carcinoma cells through the EGFR pathway and its downstream target ERK in cancer cells [52].…”

Section: Activation Of Cell-stimulating Growth Factors and Cytokines mentioning

confidence: 99%

“…Co-culture of M2 macrophages that were polarized from THP1 monocytes with oral cancer or head and neck squamous cancer cells induced the EMT of carcinoma cells through the EGFR pathway and its downstream target ERK in cancer cells [52]. Zinc finger E-box-binding homeobox 1 (ZEB1), a key transcription factor to induce EMT in cancer cells, has been shown to communicate between cancer cells and TAMs for promoting tumor progression [53]. Expression of ZEB1 in macrophages polarized them to become an F4/80 low pro-tumor phenotype and contributed to chemoresistance in mice of ovarian cancer.…”

Section: Activation Of Cell-stimulating Growth Factors and Cytokines mentioning

confidence: 99%

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Signaling of Macrophages that Contours the Tumor Microenvironment for Promoting Cancer Development

Messex

Byrd

Liou

2020

Cells

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The immune response is critical in the maintenance of an organism's health. The immune response can be broken down into two groups. The innate response, which is fast-acting and rids the body of most foreign material before infection occurs, and the adaptive response, a more specific defense against pathogen composed mostly of antibody production and killer cells. Linking the two responses via cytokine and chemokine secretion are macrophages, motile phagocytic cells that ingest and present foreign material playing a role in the innate and adaptive immune response. Although macrophages are necessary for the survival of an organism, studies have also shown macrophages play a more sinister role in the initiation, progression, and metastasis in tumorous cells. In this comprehensive review, we show how macrophages induce such a response through abnormal cellular signaling and creating a cellular microenvironment conducive for tumor growth and metastasis, as well as the future outlook of this field.

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Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles

Cited by 118 publications

References 65 publications

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

Cross‐talk between ovarian cancer cells and macrophages through periostin promotes macrophage recruitment

Signaling of Macrophages that Contours the Tumor Microenvironment for Promoting Cancer Development

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