Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

Germano, Giovanni; Frapolli, Roberta; Belgiovine, Cristina; Anselmo, Achille; Pesce, Samantha; Liguori, Manuela; Erba, Eugenio; Uboldi, Sarah; Zucchetti, Massimo; Pasqualini, Fabio; Nebuloni, Manuela; Rooijen, Nico van; Mortarini, Roberta; Beltrame, Luca; Marchini, Sergio; Nerini, Ilaria Fuso; Sanfilippo, Roberta; Casali, Paolo G.; Pilotti, Silvana; Galmarini, Carlos M.; Anichini, Andrea; Mantovani, Alberto; D’Incalci, Maurizio; Allavena, Paola

doi:10.1016/j.ccr.2013.01.008

Cited by 757 publications

(646 citation statements)

References 67 publications

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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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Section: Innate Immune Cellsmentioning

confidence: 99%

“…Studies in xenograft tumor models using human breast cancer cell lines have also shown that CSF1 neutralization together with a triple chemotherapy modality (cyclophosphamide, methotrexate, and 5-FU) reverses chemoresistance [30]. Another chemotherapeutic drug, trabectedin, induces apoptosis specifically in monocytes and macrophages, and this forms a key component of its anti-tumor activity [31].Although these studies reveal that macrophages counteract the efficacy of various chemotherapeutics and suggest that the synergism between TAM inhibition and chemotherapy may be beneficial for several types of cancer, it will be important for future experiments to focus on resistance mechanisms within the immune system. The studies above combining chemotherapy with TAM blockade show only a transient effect on tumor growth; these tumors do not regress and they eventually grow out [22,23,29,30].…”

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confidence: 99%

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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“…TAMs are deeply involved in cancer survival and proliferation. Thus, targeting these macrophages [42] can prove to be an important therapeutic strategy for HCC. Most drugs, up to now, aim to block signaling pathways to inhibit pro-tumor factors in stromal cells.…”

Section: Future Directions On Targeting Tams In Hccmentioning

confidence: 99%

Tumor-Associated Macrophages, Inflammation and Pathogenesis of Hepatocellular Carcinoma

Lewis¹

2014

J Mol Genet Med

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Chronic inflammatory state is linked to the emergence of hepatocellular carcinoma, one of the most common and aggressive cancers worldwide. The complex microenvironment of tumor changes dynamically and consequently affects the pathological process. Understanding the immunological milieu of tumor in hepatocellular carcinoma can have crucial repercussions on how we see liver cancer and help plan for future cancer treatments. Taking part in this dynamic microenvironment, macrophages play a vital role in tumor growth and proliferation, cancer survival, metastasis and angiogenesis. In this review, we discuss the place and the current understanding of tumorassociated macrophages and their role in the process of hepatocarcinogenesis. In addition, we present directions for research targeting macrophage plasticity for future anti-tumor therapeutic approaches.

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Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

Cited by 757 publications

References 67 publications

Inflammation and skeletal metastasis

Inflammation and skeletal metastasis

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Tumor-Associated Macrophages, Inflammation and Pathogenesis of Hepatocellular Carcinoma

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