Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression

Ide, Hisamitsu; Seligson, David B.; Memarzadeh, Sanaz; Li, Xin; Horvath, Steve; Dubey, Purnima; Flick, Maryann B.; Kacinski, Barry M.; Palotie, Aarno; Witte, Owen N.

doi:10.1073/pnas.222537099

Cited by 92 publications

(88 citation statements)

References 49 publications

(47 reference statements)

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“…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. The mechanisms whereby CSF1R overexpression might promote renal carcinogenesis may be similar to those of other neoplasms.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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

et al. 2009

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“…Total RNA was isolated using TRIzol reagent (Life Technologies TM ) and subjected to RT-PCR using specific primers sets for human CSF1 and CSF1R (30 pmol each) as previously described. 7,20 To determine CSF1 protein production, A549 cells grown to 80% confluence were placed in serum-free (SF) medium and, at the indicated time points, cell-free conditioned medium was assayed for CSF1 using an ELISA that specifically detects human CSF1 (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

“…The effect of CSF1 is mediated via the c-fms tyrosine kinase receptor (CSF1R) that is expressed on mononuclear phagocytes, osteoclasts, and some cancer cells. [4][5][6][7] Abnormally high CSF1 and/or CSF1R have been associated with aggressive behavior of malignancies, including breast, prostate, and ovarian cancer. 6,7 The importance of CSF1 in cancer metastasis has been shown in humans with lung cancer and in rodent models.…”

mentioning

confidence: 99%

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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“…Recently, additional growth factor receptors and their ligands have been studied in normal prostatic epithelial cells. Receptors for colony-stimulating factor (CSF)-1 were expressed, albeit at relatively low levels (Ide et al 2002). Parallel studies of mouse prostate development demonstrated epithelial expression of CSF-1R during the protrusion of prostatic buds from the urogenital sinus and during the prepubertal and androgen-driven proliferative expansion and branching of the glands, suggesting a developmental role for this tyrosine kinase.…”

Section: Stem Cellsmentioning

confidence: 97%

Primary cell cultures as models of prostate cancer development

Peehl¹

2005

Endocr Relat Cancer

152

142

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This review focuses on primary cultures of human prostatic epithelial cells and their applications as models of normal and malignant biological behavior. Current abilities to culture cells from normal tissues, from premalignant dysplastic lesions (prostatic intraepithelial neoplasia), from primary adenocarcinomas, and from metastases are described. Evidence for representation of the interrelated cells of the normal prostatic epithelium -stem cells, basal epithelial cells, secretory epithelial cells, transit amplifying cells and neuroendocrine cells -in primary cultures is presented. Comparisons between normal and cancer-derived primary cultures are made regarding biological activities relevant to carcinogenesis, such as proliferation, apoptosis, differentiation, senescence, adhesion, migration, invasion, steroid hormone metabolism, other metabolic pathways and angiogenesis. Analyses of tumor suppressor activity, differential gene expression and cytogenetics in primary cultures have revealed changes relevant to prostate cancer progression. Preclinical studies with primary cultures have provided information useful for designing new strategies for chemoprevention, chemotherapy, cytotoxin therapy, radiation therapy, gene therapy and imaging. While the behavior of normal primary cultures is often used as a basis for comparison with established, immortal prostate cancer cell lines, the most informative studies are performed with donor-matched pairs of normal and malignant primary cultures, grown under identical conditions. Challenges that remain to be addressed if the full potential of primary cultures as a model system is to be realized include isolation, culture and characterization of stem cells, improved methodology to induce or maintain a fully differentiated, androgen-responsive phenotype, and identification of cell surface antigens or other markers with which to purify pure populations of live cancer or premalignant cells apart from non-malignant epithelial cells prior to culture.

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Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression

Abstract: Colony-stimulating factor-1 receptor (CSF-1R

Cited by 92 publications

References 49 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

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

Primary cell cultures as models of prostate cancer development

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