Postsurgical Adjuvant Tumor Therapy by Combining Anti-Angiopoietin-2 and Metronomic Chemotherapy Limits Metastatic Growth

Srivastava, Kshitij; Hu, Junhao; Korn, Claudia; Savant, Soniya; Teichert, Martin; Kapel, Stephanie S.; Jugold, Manfred; Besemfelder, Eva; Thomas, Markus; Pasparakis, Manolis; Augustin, Hellmut G.

doi:10.1016/j.ccell.2014.11.005

Cited by 124 publications

(137 citation statements)

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“…Antiinflammatory therapies have been evaluated with success for targeting tumor progression and metastasis, and they are associated with reduced infiltration of bone marrow-derived myeloid cells and the prometastatic macrophages. 17,[186][187][188][189][190] A different approach to target metastasis involves the direct stimulation of antitumor immunity. For example, transformation of macrophages from M2 to M1 type has been demonstrated to recruit cytotoxic T cells and elicit antitumor responses.…”

Section: Resultsmentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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Section: Resultsmentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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“…In patients with breast cancer, Ang2 expression in tumors is associated with lymph node involvement and poor prognosis (27) and serum Ang2 levels present with diagnostic and prognostic potential for human breast cancer (28). Ang2 is implicated in the metastasis of breast cancer (16,24,(29)(30)(31)(32) and emerges as an attractive therapeutic target for breast cancer metastasis (33). However, the complex signaling of Ang2 in the tumor microenvironment and its pleiotropic effect on endothelial cells and perivascular cells may limit the efficacy and response to Ang2-targeted therapies, requiring a deeper understanding of the effect of the Ang2 signaling network on vascular remodeling and cancer cell behavior.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

Kim¹,

Sampaio²,

Lundy³

et al. 2016

JCI Insight

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Section: Immune Cell Function Following Vascular-targeting Agentsmentioning

confidence: 99%

“…In addition, ANGPT2 inhibitors reduce lung metastasis in spontaneous breast cancer metastasis models [140,144]. The effect of ANGPT2 inhibitors on metastasis most likely occurs during the late stages of the metastatic cascade when monocyte-derived macrophages facilitate angiogenesis [145], since neutralization of ANGPT2 decreases CCL2-dependent monocyte recruitment to lungs and ICAM-mediated monocyte adhesion to endothelial cells [144]. Furthermore, inhibition of recruitment of TIE2-expressing macrophage to transplanted tumors via CXCR4 blockade amplifies the tumor inhibitory effect of the vascular-damaging agent, combretastatin, indicating that this subset of TAMs counteracts the efficacy of combretastatin [138].…”

Section: Immune Cell Function Following Vascular-targeting Agentsmentioning

confidence: 99%

“…In GEMM and transplantable models of breast cancer, paclitaxel in combination with the TAM targeted antibody, anti-CSF1R, as well as radiotherapy and anti-CTLA4 inhibits the formation of spontaneous metastasis [22,23,175,202]. Neutralization of Angiopoietin 2 (ANGPT2) also reduces metastasis in breast cancer models by preventing TAM association with endothelial cells and angiogenesis [140] as well as CCL2-dependent recruitment of monocytes to metastatic lesions in lung [144,145]. TAMs resident in pancreatic tumors suppress CD8 + T cell functions, and targeting TAMs via anti-CSF1R together with gemcitabine decreases liver metastasis through reactivation of CD8 + T cells [29].…”

Section: Glossary Boxmentioning

confidence: 99%

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Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Postsurgical Adjuvant Tumor Therapy by Combining Anti-Angiopoietin-2 and Metronomic Chemotherapy Limits Metastatic Growth

Cited by 124 publications

References 50 publications

Inflammation and skeletal metastasis

Inflammation and skeletal metastasis

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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