The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases

Minami, Takashi; Jiang, Shuying; Schadler, Keri; Suehiro, Jun Ichi; Osawa, Tsuyoshi; Oike, Yuichi; Miura, Mai; Naito, Makoto; Kodama, Tatsuhiko; Ryeom, Sandra

doi:10.1016/j.celrep.2013.07.021

Cited by 92 publications

(87 citation statements)

References 30 publications

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“…In addition, we detected other altered E2F target genes known to function in tumor angiogenesis. Previous studies have demonstrated that Angpt2 can promote angiogenesis (49,50,71) and tumor cell invasion (51,(72)(73)(74). In addition, E2F1 tumors have significantly low levels of Cyr61, and blocking of Cyr61 function decreased metastasis in a xenograft of the MDA-MB231 human breast cancer cell line (52).…”

Section: Discussionmentioning

confidence: 99%

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

112

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bWhile the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control. Breast cancer remains a leading cause of death for women, with high mortality rates attributed to distant metastasis (1). To simplify the examination of signaling pathway requirements in metastatic breast cancer, research has turned to mouse model systems. Previous studies with mouse models of breast cancer have begun to reveal the mechanistic features of breast cancer metastasis, and in vivo selection has demonstrated the ability to select for tumors that metastasize to a specific location (2-5). Yet we lack a complete understanding of the pathways that govern the molecular circuitry of metastatic breast cancer. One model that has been integral in examining metastatic progression is the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) model. Originally described as exhibiting rapid tumor onset and a high degree of pulmonary metastasis (6), this model has since been used to examine a number of facets of metastasis. For example, work using the MMTV-PyMT model led to the discovery of the prometastatic signaling exchange between tumors and macrophages (7). In addition, the metastatic contributions of individual signaling molecules, such as transforming growth factor ␤ (TGF-␤), AKT, and adiponectin, have also been uncovered using this model (8-10). Given that PyMT can activate multiple signaling pathways with relevance to human breast cancer (11), there is clear utility in this model for characterizing pathways that contribute to breast cancer metastasis.The identification of signaling pathways contributing to tumor progression has bee...

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Section: Discussionmentioning

confidence: 99%

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

112

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“…Similarly, treatment with an antibody targeting VEGF receptor 2 (VEGFR2) increased the efficacy of HER2-targeted therapies against established brain metastases from HER2-positive breast cancer in a mouse xenograft model 43 . In animal models, VEGF also exerts pro-metastatic effects through activation of the calcineurin–nuclear factor of activated T cells (NFAT) pathway via upregulation of ANG2 expression in ECs 44 . In line with these preclinical data, high levels of ANG2 expression determined by transcriptomic analysis of tumour samples correlate with an increased metastatic burden in patients with breast cancer 45 .…”

Section: The Abnormal Tumour Vasculaturementioning

confidence: 99%

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

et al. 2018

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Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

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“…Studies have also been performed examining the microenvironment of the premetastatic site or niche. Loss of DSCR1, an endogenous calcineurin inhibitor, leads to excessive calcineurin/NFAT/angiopoietin-2 (ANG-2) pathway activation in lung endothelium and the establishment of lung metastasis [123]. Increased VEGF level in the lung microenvironment triggers calcineurin/NFAT/ANG-2 signaling activation and promotes angiogenesis in the pre-metastatic niche.…”

Section: Nfats In the Tumor Microenvironmentmentioning

confidence: 99%

Nuclear factor of activated T cells in cancer development and treatment

et al. 2015

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Since nuclear factor of activated T cells (NFAT) was first identified as a transcription factor in T cells, various NFAT isoforms have been discovered and investigated. Accumulating studies have suggested that NFATs are involved in many aspects of cancer, including carcinogenesis, cancer cell proliferation, metastasis, drug resistance and tumor microenvironment. Different NFAT isoforms have distinct functions in different cancers. The exact function of NFAT in cancer or the tumor microenvironment is context dependent. In this review, we summarize our current knowledge of NFAT regulation and function in cancer development and treatment. NFATs have emerged as a potential target for cancer prevention and therapy.

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The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases

Cited by 92 publications

References 30 publications

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Nuclear factor of activated T cells in cancer development and treatment

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