Macrophages Promote the Invasion of Breast Carcinoma Cells via a Colony-Stimulating Factor-1/Epidermal Growth Factor Paracrine Loop

Goswami, Sumanta; Wyckoff, Jeffrey; Cammer, Michael; Cox, Dianne; Pixley, Fiona J.; Stanley, E. Richard; Segall, Jeffrey E.; Condeelis, John S.

doi:10.1158/0008-5472.can-04-1853

Cited by 648 publications

(602 citation statements)

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“…Abnormally high CSF1R expression has been associated with aggressive behavior and poor outcome in a variety of malignancies, including breast, 22,23 endometrial, 24,25 ovarian, 26,27 and prostate cancers. 28 The follow-up time in this series is still relatively short to allow a meaningful evaluation of the prognostic value of CSF1R overexpression in renal cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies indicate that autocrine and paracrine interaction of CSF1R and its ligand CSF1 may participate in the biology of breast cancer, being associated with tumor progression and metastasis. 22,23,29 In ovarian cancer autocrine intracellular or extracellular interactions between CSF1R and CSF1 produced by the tumor cells are more relevant than paracrine effects of stromal CSF1. 26,27 Concomitant expression of CSF1R and CSF1 was also observed in endometrial cancer cells and it is absent in the adjacent normal tissue.…”

Section: Discussionmentioning

confidence: 99%

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CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

et al. 2009

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Renal cell carcinomas comprise a heterogeneous group of tumors. Of these, 80% are clear cell renal cell carcinomas, which are characterized by loss of 3p, often with concomitant gain of 5q22qter. Although VHL is considered the main target gene of the 3p deletions, none has been identified as the relevant target gene for the 5q gain. We have studied 75 consecutive kidney tumors and paired normal kidney samples to evaluate at the genomic and expression levels the tyrosine kinase genes CSF1R and PDGFRB as potential targets in this region. Our findings show that RNA expression of CSF1R, but not of PDGFRB, was significantly higher in clear cell renal cell carcinomas than in normal tissue samples, something that was corroborated at the protein level by immunohistochemistry. The CSF1R staining pattern in clear cell renal cell carcinomas was clearly different from that observed in other renal cell carcinomas, suggesting its potential usefulness in differential diagnosis. FISH analysis demonstrated whole chromosomal gain and relative CSF1R/PDGFRB copy number gain in clear cell renal cell carcinomas, which might contribute to CSF1R overexpression. Finally, one polymorphism and two novel mutations were identified in CSF1R in clear cell renal cell carcinoma patients. Our data allow us to conclude that CSF1R plays a relevant role in clear cell renal cell carcinoma carcinogenesis and raise the possibility that CSF1R may represent a future valuable therapeutic target in these patients. Keywords: renal cell carcinoma; CSF1R oncogene; mutation; overexpression Renal cell carcinomas comprise a heterogeneous group of tumors that represent about 3% of all malignancies in adults in the Western countries. 1 Clear cell renal cell carcinomas, which represent about 80% of all kidney tumors, are characterized by the loss of the short arm of chromosome 3 (3p), often with a concomitant gain of 5q22qter as the result of an unbalanced 3p;5q translocation. 2 Several genes have been presented as the targets of the 3p deletions seen in this tumor type, with emphasis for VHL (3p25Bp26). In fact, germline mutations of VHL underlie the von Hippel-Lindau syndrome (which includes clear cell renal cell carcinoma as one of its features), whereas somatic inactivation of this gene has been demonstrated in the great majority of sporadic clear cell renal cell carcinomas. 3,4 On the other hand, no target genes have been identified for the 5q22qter gain, the second most common copy number change in clear cell renal cell carcinomas. 2,5 The colony-stimulating factor-1 receptor (CSF1R) gene located in 5q33 is a potential target for this chromosomal gain in clear cell renal cell carcinomas. CSF1R is a transmembrane tyrosine kinase receptor and the CSF1R/CSF1 receptor/ligand complex has essential physiological functions in monocyte and macrophage differentiation, embryonic implantation, placental development, and lactogenic differentiation of the human breast. 6 Codons 301 and 969 located in CSF1R exons 7 and 22, respectively, have been shown to be mutated in he...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

et al. 2009

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“…25 It was determined that macrophages aided breast cancer cell invasion into surrounding tissue by forming a paracrine communication loop between colony-stimulating factor 1 (CSF-1)-secreting cancer cells and EGF-secreting macrophages. 15 Blockade of either EGF or CSF-1 signaling was able to inhibit this invasion. Invasion induced by other chemotactic stimuli such as CXCL12 and heregulin ␤1 (HRG␤1) also relied on this paracrine loop.…”

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confidence: 97%

“…Stromal cells are known to release chemotactic signals that drive invasion of tumor cells further into host stoma. For example, tumor-associated macrophages, fibroblasts, or platelets can produce EGFR ligands such as EGF, [15][16][17] whereas tumor-associated fibroblasts can produce CXCL12. 18 Macrophages express the CXCL12 receptor CXCR4, whereas tumor cells can express both EGFR and CXCR4.…”

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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

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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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Microenvironmental modulation of the developing tumour: an immune‐stromal dialogue

2020

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Macrophages Promote the Invasion of Breast Carcinoma Cells via a Colony-Stimulating Factor-1/Epidermal Growth Factor Paracrine Loop

Cited by 648 publications

References 22 publications

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

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

Microenvironmental modulation of the developing tumour: an immune‐stromal dialogue

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