Overexpression of the Colony-Stimulating Factor (CSF-1) and/or Its Receptor <b>
                     <i>c-fms</i>
                  </b> in Mammary Glands of Transgenic Mice Results in Hyperplasia and Tumor Formation

Kirma, Nameer B.; Luthra, Roopa; Jones, Jeremy O.; Liu, Ya Guang; Nair, Hareesh B.; Mandava, Usha; Tekmal, Rajeshwar Rao

doi:10.1158/0008-5472.can-03-2971

Cited by 42 publications

(39 citation statements)

References 14 publications

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“…40 Mice with ovarian cancer cells expressing high levels of CSF1 showed widespread visceral and distant metastasis compared to mice with control cells. 9 Overexpression of CSF1 in the mammary cancer-susceptible polyoma middle T antigen mice resulted in acceleration of malignant progression and metastasis. 10 Conversely, the absence of CSF1 in op/op mice in the polyoma middle T antigen background retarded mammary tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…In rodents with ovarian or breast cancer, overexpression of CSF1 accelerated tumor progression and 1 metastasis. 8,9 Patients with lung cancer show increased circulating CSF1 and high levels correlate with tumor progression and poor prognosis. 10 Lung cancer cells including the human A549 lung adenocarcinoma cell line express CSF1R, CSF1 mRNA, and protein, and, in vitro, CSF1 increases A549 proliferation and invasion.…”

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confidence: 99%

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Colony-stimulating factor 1 potentiates lung cancer bone metastasis

Hung¹,

Horn

Woodruff

et al. 2014

Laboratory Investigation

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Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors. Patients with lung cancer have increased CSF1 in serum and high levels are associated with poor survival. Adenocarcinomas metastasize rapidly and many patients suffer from bone metastasis. Lung cancer stem-like cells sustain tumor growth and potentiate metastasis. The purpose of this study was to determine the role of CSF1 in lung cancer bone metastasis and whether inhibition of CSF1 ameliorates the disease. Human lung adenocarcinoma A549 cells were examined in vitro for CSF1/CSF1R. A549-luc cells were injected intracardiac in NOD/SCID mice and metastasis was assessed. To determine the effect of CSF1 knockdown (KD) in A549 cells on bone metastasis, cells were stably transfected with a retroviral vector containing short-hairpin CSF1 (KD) or empty vector (CT). Results showed that A549 cells express CSF1/CSF1R; CSF1 increased their proliferation and invasion, whereas soluble CSF1R inhibited invasion. Mice injected with A549-luc cells showed osteolytic bone lesions 3.5 weeks after injection and lesions increased over 5 weeks. Tumors recapitulated adenocarcinoma morphology and showed osteoclasts along the tumor/bone interface, trabecular, and cortical bone loss. Analyses of KD cells showed decreased CSF1 protein levels, reduced colony formation in soft agar assay, and decreased fraction of stem-like cells. In CSF1KD mice, the incidence of tumor metastasis was similar to controls, although fewer CSF1KD mice had metastasis in both hind limbs. KD tumors showed reduced CSF1 expression, Ki-67 þ cells, and osteoclasts. Importantly, there was a low incidence of large tumors 40.1 mm 2 in CSF1KD mice compared with control mice (10% vs 62.5%). This study established a lung osteolytic bone metastasis model that resembles human disease and suggests that CSF1 is a key determinant of cancer stem cell survival and tumor growth. Results may lead to novel strategies to inhibit CSF1 in lung cancer and improve management of bone metastasis.Laboratory Investigation (2014) 94, 371-381; doi:10.1038/labinvest.2014.1; published online 27 January 2014 KEYWORDS: bone; cancer; CSF1; lung; metastasis Lung cancer is the leading cause of cancer deaths world wide. 1 The majority of lung cancers are non-small-cell type and, of those, adenocarcinoma is the most common. These tumors have a high mortality rate and metastasize rapidly, often within months of diagnosis, with 60-70% of patients developing bone metastasis. 2,3 Lesions are predominantly osteolytic, involving vertebrae, rib, pelvis, and femur that lead to significant morbidity from spinal cord compression, pathologic fractures, and intractable pain. Metastasis to bone is associated with a poor prognosis and a mean survival of 9.7 months. 2 Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors to bone. The effect of CSF1 is mediated via the c-fms tyrosine kinase receptor (CSF1R) that is expressed on mononuclear ph...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

Hung¹,

Horn

Woodruff

et al. 2014

Laboratory Investigation

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“…In osteoclasts RANK expression is regulated by macrophage colony-stimulating factor 1 (3), transforming growth factor ␤ (26), and the transcription factor PU.1 (31). Both colony-stimulating factor 1 and transforming growth factor ␤ have important roles in mammary gland development (29,35,47); additional experiments are required to determine if these same factors regulate RANK expression in the mammary gland.…”

Section: Discussionmentioning

confidence: 99%

RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini

Gonzalez-Suarez

Branstetter²,

Armstrong³

et al. 2007

Molecular and Cellular Biology

113

107

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RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cell proliferation during pregnancy, impaired differentiation of lobulo-alveolar structures, decreased expression of the milk proteins ␤-casein and whey acidic protein, and deficient lactation. We also show that treatment of three-dimensional in vitro cultures of primary mammary cells from MMTV-RANK mice with RANKL results in increased proliferation and decreased apoptosis in the luminal area, resulting in bigger acini with filled lumens. Taken together, these results suggest that signaling through RANK not only promotes proliferation but also inhibits the terminal differentiation of mammary epithelial cells. Moreover, the increased proliferation and survival observed in a three-dimensional culture system suggests a role for aberrant RANK signaling during breast tumorigenesis.The tumor necrosis factor (TNF) family member RANKL and its receptor RANK are key regulators of osteoclast differentiation and activation (16,30). The balance between RANKL, RANK, and osteoprotegerin (OPG), a soluble decoy receptor that competes with RANK for binding to RANKL (32), regulates osteoclast differentiation and activation and therefore bone remodeling and mobilization of calcium from the skeleton (27). In mice, RANK and RANKL are also essential for the development of the mammary gland during pregnancy (18), in particular, for the formation of lobuloalveolar structures after pregnancy day 14 (P14) which are required for a functional lactating mammary gland.Deregulation in the RANKL/OPG system has been reported in malignant bone disease including bone metastasis and humoral hypercalcemia of malignancy (13,21,23). Numerous lines of evidence in animal models indicate that blocking RANK/RANKL interaction effectively prevents tumor-induced hypercalcemia or reduces tumor-induced bone lesions, due to its critical role in osteoclast differentiation and activation (reviewed in references 38 and 41). While RANK expression has been detected in breast cancer lines and in primary tumors including breast tumors (45) and may play a functional role in tumor cell migration and metastasis to the bone (24), it is not clear whether activation of the RANK/RANKL pathway may also contribute to primary tumor growth.The mammary gland defects observed in RANK-and RANKL-deficient mice support the notion that the RANK/ RANKL pathway plays an active role in mammary cell proliferation and survival; however, the direct effect of increased RANK signaling in mammary cells is unknown. To determine if activation of the RANK/RANKL pathway can directly increase proliferation or surv...

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“…One common feature of epithelial cancers of breast, lung, pancreatic, endometrial, and ovarian origin is the overexpression of the secreted form of macrophage colony-stimulating factor, CSF-1 (4-kb mRNA isoform) and its receptor, c-fms (3)(4)(5)(6). The coexpression of CSF-1 and c-fms is usually a sign of poor prognosis and can be used as a diagnostic marker of the stage of tumor growth (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3′ Untranslated Region of Colony-Stimulating Factor–1 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype

et al. 2005

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The overexpression of the colony-stimulating factor-1(CSF-1) by epithelial ovarian cancer cells enhances invasiveness and metastatic properties, contributing to the poor prognosis of the patients. It has been suggested that CSF-1 3Vuntranslated region containing AU-rich elements (ARE) could regulate CSF-1 posttranscriptional expression and be responsible for its aberrant abundance in such cancer cells. In this study, normal (NOSE.1) and malignant (Hey) ovarian epithelial cells were used to examine CSF-1 expression and regulation. CSF-1 overexpression in Hey cells was found to associate with increased invasiveness, motility, urokinase activity, and virulence of tumorigenicity, compared with NOSE.1 cells, which expressed little CSF-1. CSF-1 ARE was further found to serve as an mRNA decay element that correlates with downregulation of protein translation. Moreover, such downregulation was found more prominent in NOSE.1 than in Hey cells, suggesting differences in posttranscriptional regulation. As a variety of trans-acting factors [AU-binding protein (AUBP)] are known to modulate messenger stability through binding to such elements, we examined the protein content of both cell lines for their ability to bind the CSF-1 ARE. Our results strongly suggested the abundance of such AUBP activity in Hey cells. We isolated a 37-kDa AUBP, which was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To summarize, our study identified GAPDH as an AUBP abundant in Hey cells, where it binds to CSF-1 ARE that imparts mRNA decay. These data suggest that GAPDH binding to CSF-1 ARE sequence prevents CSF-1 mRNA decay and subsequent down-regulation of CSF-1 protein translation, leading to CSF-1 overexpression and increased metastatic properties seen in ovarian cancer. (Cancer Res 2005; 65(9): 3762-71)

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Overexpression of the Colony-Stimulating Factor (CSF-1) and/or Its Receptor c-fms in Mammary Glands of Transgenic Mice Results in Hyperplasia and Tumor Formation

Cited by 42 publications

References 14 publications

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini

Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3′ Untranslated Region of Colony-Stimulating Factor–1 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype

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