A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors

Wyckoff, Jeffrey; Wang, Weigang; Lin, Elaine Y.; Wang, Yarong; Pixley, Fiona J.; Stanley, E. Richard; Graf, Thomas; Pollard, Jeffrey W.; Segall, Jeffrey E.; Condeelis, John S.

doi:10.1158/0008-5472.can-04-1449

Cited by 1,035 publications

(1,060 citation statements)

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“…Depletion of macrophages effectively blocked metastasis in a mouse model [7]. Thus, disrupt of TAM function will provide a novel approach to develop anti-cancer therapies.Recruitment of macrophages to the proximity of tumors was mediated by CSF-1, a growth factor, secreted by tumor cells [6]. CSF-1 also stimulates the proliferation, differentiation, and survival of macrophages [8].…”

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confidence: 99%

Akt2 is required for macrophage chemotaxis

Zhang

Guo

et al. 2009

Eur J Immunol

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Tumor-associated macrophages play an important role in tumorigenesis and metastasis. Trafficking of macrophages to the proximity of tumors is mediated by CSF-1, a growth factor. In this study, we investigated the role of PKB/Akt in CSF-1-induced macrophage migration. Disruption of Akt2 expression by small interference RNA impaired chemotaxis of both THP-1 cells and mouse peritoneal macrophages. Phosphorylation of PKCf, an essential component in chemotaxis signaling pathway, was reduced. LIMK/Cofilin, downstream of PKCf, regulated cytoskeleton rearrangement during cell migration. Disruption of Akt2 expression inhibited CSF-1-induced LIMK/Cofilin phosphorylation, which contributed to defects in actin polymerization and chemotaxis. Furthermore, MCP-1, a chemokine, -induced macrophage chemotaxis was also impaired. Taken together, our results demonstrated that Akt2 plays an essential role in both CSF-1-and chemokine-induced chemotaxis of macrophages.Key words: Chemokine . CSF-1 . Metastasis . Tumor-associated macrophages IntroductionChronicle inflammation promotes, sometimes even induces, tumorigenesis [1,2]. Tumor attracts macrophages and induces their differentiation by secreting . In comparison with conventional macrophages, tumor-associated macrophage (TAM) cells exhibit poor antigen-presenting capability, produce factors that suppress T-cell proliferation and activity, and are generally better adapted to scavenging debris, promoting angiogenesis, repairing and remodeling wounded/damaged tissues [3]. Recent studies show that TAM cells also play an essential role in inducing invasion and metastasis of breast tumors [4,5]. TAM cells secrets EGF to induce the proliferation and invasion of surrounding tissues by tumor cells [6]. Eventually, migratory cancer cells follow EGF gradient, enter the circulation, and spread throughout the body. Depletion of macrophages effectively blocked metastasis in a mouse model [7]. Thus, disrupt of TAM function will provide a novel approach to develop anti-cancer therapies.Recruitment of macrophages to the proximity of tumors was mediated by CSF-1, a growth factor, secreted by tumor cells [6]. CSF-1 also stimulates the proliferation, differentiation, and survival of macrophages [8]. Macrophages stimulated with CSF-1 show immediate cell polarization, actin reorganization, and migration to the CSF-1 secreting tumor cells [9]. Extensive studies have revealed the molecular mechanism of chemokine receptor, a subfamily of G-protein-coupled receptors, -mediated leukocyte trafficking during inflammation [10,11]. However, the signal transduction pathway that regulates CSF-1-induced macrophage migration is still largely unknown. Investigating molecular mechanism of CSF-1-mediated macrophage chemotaxis will provide new insights to block the formation and accumulation of TAM cells.The Akt/PKB family, Akt1, 2, and 3, plays a critical role in regulating cell growth, proliferation, survival, and metabolism [12,13]. Akt1 and 2 are expressed in most cell types and tissues 894while Akt3 shows a more r...

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confidence: 99%

Akt2 is required for macrophage chemotaxis

Zhang

Guo

et al. 2009

Eur J Immunol

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“…Previous studies with breast cancer models have shown that macrophages comigrate with cancer cells in response to EGF stimulation in this in vivo invasion assay. 15,23,24 To assess macrophage comigration in HNSCC tumor models, the invasive cells collected from tumors were fixed and stained with a pan-cytokeratin antibody to detect tumor cells and an F4/80 antibody to detect macrophages ( Figure 3A). The relatively weak F4/80 staining is consistent with our previous studies in which the permeabilization required for detection of cytokeratin may reduce the amount of F4/80 detected.…”

Section: Egf Stimulates In Vivo Invasion Of Head and Neck Orthotopicmentioning

confidence: 99%

“…6 cer. 15,23,24 FaDu and UMSCC47 cells were injected into the floor of the mouth of nude mice as orthotopic models of HNSCC. We found that EGF stimulated in vivo invasion of both tumors.…”

Section: In Vivo Invasion Of Hnscc 2861mentioning

confidence: 99%

“…20,39,40 In 2004, we described a synergistic interaction between macrophages and breast tumor cells during tumor cell invasion in vivo. 24 This interaction relies on a paracrine communication loop between tumor cells and macrophages. In those studies, we found that breast tumor cells secrete CSF-1, which stimulates macrophages to secrete EGF, thereby enhancing invasion of breast tumor cells.…”

Section: In Vivo Invasion Of Hnscc 2861mentioning

confidence: 99%

“…6,22 In a study of 102 HNSCC patients, macrophage count at the primary tumor correlated positively with lymph node metastasis and stage, and was found to be an independent predictor of lymph node metastasis. 22 We have previously demonstrated macrophage-dependent tumor invasion in breast cancer animal models 15,23,24 based on an in vivo invasion assay. This assay collects invasive cells from primary xenograft and transgenic tumors in response to chemotactic cues.…”

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In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages

Смирнова

Adomako

Locker

et al. 2011

The American Journal of Pathology

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Invasion of tumor cells into the local stroma is an important component in cancer progression.Here we report studies of the in vivo invasion of head and neck squamous cell carcinoma (HNSCC) cells in response to applied gradients of a growth factor [epidermal growth factor (EGF)] and a chemokine (CXCL12), using orthotopic floor-of-mouth models. Analysis of the invading cells indicated that >75% of them were tumor cells, about 15% macrophages, and <10% were unidentified. Surprisingly, although macrophages invaded together with tumor cells, macrophage contributions were not required for HNSCC invasion. CXCL12-induced in vivo invasion of HNSCC cells was also observed and found to occur via a unidirectional transactivation of epidermal growth factor receptor (EGFR) through CXCR4. Inhibition of tumor necrosis factor-␣-converting enzyme using TNF-␣ protease inhibitor-2 selectively inhibited CXCL12-induced invasion but not EGF-induced invasion, consistent with CXCL12 activation of EGFR via release of EGFR ligands. Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common types of cancer in the world, with over 500,000 new cases per year and 250,000 deaths worldwide as estimated by the World Health Organization. This includes 48,000 new cases and 11,260 deaths in 2009 from HNSCC in the United States. 1 HNSCC originates from mucosal tissues of the upper aerodigestive tract and spans the oral cavity to the larynx. Despite some improvements in treatment methods, the 5-year survival rate remains just above 50%. 1 Current treatments for HNSCC include single and multimodality therapies using surgical and nonsurgical approaches (chemotherapy and/or radiotherapy). 2 A key constraint that limits the ability of surgical treatment to cure HNSCC is the location-adequate margins to guarantee removal of all tumor cells are difficult to achieve in many cases without severely compromising quality of life or survival. Thus, the degree to which tumor cells have locally spread from the primary tumor can impact the likelihood of recurrence. Indeed, morphological examination of HNSCC has revealed that the pattern of tumor invasion, presence of perineural invasion, and presence of inflammatory cells correlate with clinical outcome. [3][4][5][6] Understanding the mechanisms underlying HNSCC invasion could provide an opportunity to reduce local invasion and improve patient outcome. The epidermal growth factor receptor (EGFR) is often overexpressed in HNSCC 7,8 and correlated with poor prognosis. 9 In addition to driving proliferation, the EGFR has the potential to drive invasion. EGFR ligands are chemoattractants, stimulating directly cell motility and HNSCC invasion in vitro. 10 -12 Studies of EGFR function in HNSCC in vivo have focused on tumor growth, 13,14 and direct evaluation of EGFR-mediated invasion in vivo has been poorly explored.

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Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development

Greenow

Smalley

2015

CP Pharmacology

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Breast cancer is a heterogeneous condition with no single standard of treatment and no definitive method for determining whether a tumor will respond to therapy. The development of murine models that faithfully mimic specific human breast cancer subtypes is critical for the development of patient-specific treatments. While the artificial nature of traditional in vivo xenograft models used to characterize novel anticancer treatments has limited clinical predictive value, the development of genetically engineered mouse models (GEMMs) makes it possible to study the therapeutic responses in an intact microenvironment. GEMMs have proven to be an experimentally tractable platform for evaluating the efficacy of novel therapeutic combinations and for defining the mechanisms of acquired resistance. Described in this overview are several of the more popular breast cancer GEMMs, including details on their value in elucidating the molecular mechanisms of this disorder.

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A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors

Cited by 1,035 publications

References 55 publications

Akt2 is required for macrophage chemotaxis

Akt2 is required for macrophage chemotaxis

In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages

Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development

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