Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-  dependent up-regulation of matrix metalloproteases

Hagemann, Thorsten; Robinson, Stephen H.; Schulz, Matthias; Trümper, Lorenz; Balkwill, Frances R.; Binder, Claudia R.

doi:10.1093/carcin/bgh146

Cited by 334 publications

(281 citation statements)

References 36 publications

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Section: Resultsmentioning

confidence: 99%

“…When THP-1 cells were co-cultured with MCF-7, a representative breast cancer cell line, Western blotting analysis revealed an increase in Akt phosphorylation at both 308 and 473 residues, suggesting that breast cancer cells can stimulate Akt activation in macrophage (Fig. 1B) [21,22].A small RNA interference plasmid, containing a green fluorescent protein expression cassette, was chosen from our previous experiments to disrupt Akt2 expression in MDA-MB-231 cells [23]. After selection by 0.6 mg/mL Hygromycin B for 4 wk, cells were examined by Western blotting analysis of Akt2 and designated as siAkt2/THP-1 cells.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Akt2 is required for macrophage chemotaxis

Zhang

Guo

et al. 2009

Eur J Immunol

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“…Although generally known for their tumoricidal capacity, there is growing evidence that regulatory networks within tumor tissues redirect their function into a tumor-promoting activity. We have recently shown that cocultivation with M increases invasiveness of weakly invasive breast cancer cells (33). The aim of this study was to investigate whether Wnt signaling is involved in this effect.…”

Section: Discussionmentioning

confidence: 99%

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Pukrop

Klemm

Hagemann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

320

290

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Interactions between neoplastic and stromal cells contribute to tumor progression. Wnt genes, involved in cell migration and often deregulated in cancers, are attractive candidates to regulate these effects. We have recently shown that coculture of breast cancer cells with macrophages enhances invasiveness via matrix metalloproteases and TNF-␣. Here we demonstrate that coculture of MCF-7 cells and macrophages leads to up-regulation of Wnt 5a in the latter. This was accompanied by activation of AP-1͞c-Jun in MCF-7. Recombinant Wnt 5a mimicked the coculture effect. Wnt 5a was also detectable in tumor-associated macrophages in primary breast cancers. Experiments with agonists and antagonists of Wnt signaling revealed that a functional canonical pathway in the tumor cells was a necessary prerequisite; however, noncanonical signaling via Wnt 5a and the Jun-N-terminal kinase pathway was critical for invasiveness. It was also responsible for induction of matrix metalloprotease-7, known to release TNF-␣. All these effects could be antagonized by dickkopf-1. Our results indicate that Wnt 5a is essential for macrophage-induced invasiveness, because it regulates tumor cell migration as well as proteolytic activity of the macrophages. The function of Wnt 5a as either a suppressor or promoter of malignant progression seems to be modulated by intercellular interactions. Wnt 5a detection in tumor-associated macrophages in breast cancer biopsies supports the assumption that similar events play a role in vivo.tumor microenvironment ͉ TNF-␣ ͉ matrix metalloproteases

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“…In vitro co-culture of macrophages with tumor cells has been shown to result in accelerated tumor growth [49]. TAMs express several factors, such as EGF, MMP-9, TGF-β and CXCL-14, that stimulate tumor cell proliferation and survival [50,51].…”

Section: Discussionmentioning

confidence: 99%

Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

Shabo

Olsson

Elkarim

et al. 2014

Cancer Microenvironment

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The scavenger receptor, CD163, is a macrophagespecific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffinembedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P=0.008) and unfavorable prognosis (p=0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p=0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.

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Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF- dependent up-regulation of matrix metalloproteases

Cited by 334 publications

References 36 publications

Akt2 is required for macrophage chemotaxis

Akt2 is required for macrophage chemotaxis

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer

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