Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy

Chen, Lin; Li, Jie; Wang, Fei; Dai, Chengliang; Wu, Fan; Liu, Xiaoman; Li, Taotao; Glauben, Rainer; Zhang, Yi; Nie, Guangjun; He, Yulong; Qin, Zhihai

doi:10.1158/0008-5472.can-16-1114

Cited by 77 publications

(85 citation statements)

References 44 publications

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“…Because chemotherapy induces recruitment of endothelial progenitors and TIE2 + monocyte progenitors into the tumor (10, 11, 30), and we have previously demonstrated that TIE2 hi macrophages are required for TMEM-mediated cancer cell intravasation (1), we examined the possibility that neoadjuvant paclitaxel promotes TMEM assembly and cancer cell dissemination and metastasis. We addressed this hypothesis in the following breast carcinoma models: (i) transgenic MMTV-PyMT mice bearing spontaneous breast tumors, (ii) friend virus B (FVB) mice transplanted orthotopically with tumors from MMTV-PyMT donors, and (iii) two PDX models, the HT17 and HT33, developed previously in our laboratory (31).…”

Section: Resultsmentioning

confidence: 99%

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

et al. 2017

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Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.

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Section: Resultsmentioning

confidence: 99%

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

et al. 2017

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“…Unexpectedly, we found that the EC gene Tek/Tie2, which has been used as an EC-specific Cre-driver (35) and has also been reported to be expressed in a tumor-associated macrophage/ monocyte subpopulation (36)(37)(38), was found to be expressed in some fibroblast-like cells from COLO205 tumors (Fig. 6B).…”

Section: Subpopulations Of Tumor-associated Fibroblast and Normal Fibmentioning

confidence: 80%

Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment

et al. 2018

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Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition, and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell-cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts responded to antiangiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to antiangiogenic therapies. These findings provide a framework for defining subpopulations of endothelial cells and tumor-associated fibroblasts and their rapid changes in gene expression following antiangiogenic treatment. .

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“…De Palma and colleagues demonstrated the importance of TEMs for angiogenesis by demonstrating that genetic depletion of TEMs inhibited angiogenesis and tumor growth in various subcutaneous tumor models (74), and Chen and colleagues demonstrated that Tie2 macrophages were crucial to the recovery of the tumor vasculature and recurrence of the transplanted MCA205 tumor following doxorubicin (75). Gene expression studies by Pucci and colleagues demonstrated that TEMs are a subset of TAMs and are at the extreme end of the M2 polarization spectrum (76).…”

Section: Phenotypes Of Tumor Associated Macrophagesmentioning

confidence: 99%

“…2). This M2-like polarization is driven both by tumor hypoxia (75) and by the increased expression by treated tumor cells of CSF-1 and IL-34, the ligands for the receptor CSF-1R on macrophages, thereby enhancing both their accumulation into treated tumors and polarization into an M2-like phenotype (86, 90, 92). Not only is this highly proangiogenic but also this polarization is immune suppressive.…”

Section: Improved Treatment Response By Manipulating Tams In Conjunctmentioning

confidence: 99%

The Promise of Targeting Macrophages in Cancer Therapy

Brown

Recht

Strober

2017

Clinical Cancer Research

271

225

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Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this Review we outline the importance of tumor associated macrophages (TAMs), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs and their role in blunting the efficacy to cancer treatment by radiation and anticancer drugs both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy.

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Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy

Cited by 77 publications

References 44 publications

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment

The Promise of Targeting Macrophages in Cancer Therapy

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