Overexpression of fibroblast growth factor receptor 3 in a human thyroid carcinoma cell line results in overgrowth of the confluent cultures

Onose, Hiroyuki; Emoto, Naoya; Sugihara, Hitoshi; Shimizu, Kazuo; Wakabayashi, Ichiji

doi:10.1530/eje.0.1400169

Cited by 27 publications

(15 citation statements)

References 27 publications

(31 reference statements)

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“…Recent studies have suggested that FGFR3 has a significant function in the pathogenesis and progression of some malignancies including thyroid carcinoma, bladder carcinoma, multiple myeloma, and peripheral T-cell lymphoma (Cappellen et al, 1999;Onose et al, 1999;Kastrinakis et al, 2000;Yagasaki et al, 2001;Wolff et al, 2005). Whether FGFR3 is a marker of TICs in these malignancies requires further study.…”

Section: Discussionmentioning

confidence: 99%

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

et al. 2009

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BACKGROUND: The hypothesis that malignant tumours are generated by rare populations of cancer stem cells that are more tumourigenic than other cancer cells has gained increasing credence. The objective of this study was to identify and characterise a subpopulation of human sarcoma-initiating cells. METHODS: We examined established rhabdomyosarcoma cell lines by flow cytometry. Tumourigenesis was examined by xenograft models. Real-time PCR and immunohistochemistry were performed to examine the gene expression using cell lines and biopsy specimens. RESULTS: Rhabdomyosarcoma cell lines included small populations of fibroblast growth factor receptor 3 (FGFR3)-positive cells. FGFR3-positive KYM-1 and RD cells were more strongly tumourigenic than FGFR3-negative cells. In addition, xenoengraftment of 33% of single FGFR3-positive KYM-1 cells yielded tumour formation. Stem cell properties of FGFR3-positive cells were further established by real-time PCR, which demonstrated upregulation of undifferentiated cell markers and downregulation of differentiation markers. We showed that in the absence of serum, addition of basic fibroblast growth factor maintained and enriched FGFR3-positive cells. On the other hand, ciliary neurotrophic factor reduced the proportion of FGFR3-positive cells. Real-time PCR and immunohistochemical examination revealed that embryonal rhabdomyosarcoma patient biopsy specimens were found to overexpress FGFR3. CONCLUSIONS: Our findings suggest that rhabdomyosarcoma cell lines include a minor subpopulation of FGFR3-positive sarcomainitiating cells, which can be maintained indefinitely in culture and which is crucial for their malignancy.

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Section: Discussionmentioning

confidence: 99%

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

et al. 2009

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“…22 Likewise, FGFR3 protein overexpression in a thyroid cancer cell line led to the loss of cell densitydependent growth inhibition. 23 While alternative or additional genetic alterations in human seborrheic keratoses as well as details of the involved signaling pathways need to be further determined, the mutant FGFR3 receptor represents a promising pharmaceutical target for the topical treatment of multiple seborrheic keratoses, which are still a major disfiguring problem of aging skin.…”

Section: Discussionmentioning

confidence: 99%

FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization

et al. 2007

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Somatic activating fibroblast growth factor 3 (FGFR3) mutations in human skin can cause seborrheic keratoses, one of the most frequent skin tumors in man. However, details of the involved mechanisms remain elusive. We analyzed 65 acanthotic seborrheic keratoses with varying vertical diameters for FGFR3 mutations using a SNaPshot s multiplex assay. Immunohistochemistry was performed for Ki-67, bcl-2 and FGFR3 protein in all seborrheic keratoses and 19 normal skin samples. FGFR3 mutations were detected in 37 of 65 seborrheic keratoses (57%). These mutations were found both in flat (initial) and thick seborrheic keratoses. FGFR3 mutations were significantly associated with increased age and localization on the head and neck (Po0.01). Ki-67 expression was significantly higher in seborrheic keratoses than in normal epidermis independent of the FGFR3 status (Po0.001). Furthermore, FGFR3 mutations were associated with an increased expression of bcl-2 and FGFR3 protein (Po0.05). Our results indicate that FGFR3 mutations can occur early in the pathogenesis of at least a subset of seborrheic keratoses. Increased age appears to be a risk factor for these mutations. Keywords: seborrheic keratosis; acanthosis; FGFR3 mutation; bcl-2; Ki-67 Seborrheic keratoses represent one of the most common skin tumors in man. Their prevalence increases with age. Seborrheic keratoses are detected in 80-100% of people over 50 years. 1,2 Affected individuals can show large numbers of lesions. Yeatman et al reported an average number of 69 seborrheic keratoses/person in people aged more than 75 years. Seborrheic keratoses are typically localized on the head, the trunk and the extremities with the exception of the palms and soles. They present as well-demarcated brownish plaques and later may show a verrucous surface. Their horizontal diameter ranges from a few millimeters to several centimeters. Three major histologic subtypes are known including acanthotic, hyperkeratotic and adenoid seborrheic keratoses variants. 3 Common histological features are acanthosis, papillomatosis and hyperkeratosis along with a varying degree of pigmentation. The vertical diameter (tumor thickness) of seborrheic keratoses varies considerably. Flat (initial) seborrheic keratoses frequently show gradual vertical growth within years. 3 However, malignant transformation is a very rare event in seborrheic keratoses, and the reported cases may also represent collision tumors of seborrheic keratoses and other epidermal malignancies such as basal cell carcinoma and squamous cell carcinoma. 4 Although seborrheic keratoses are very common tumors and represent one of the most disfiguring signs of skin aging, their pathogenesis is only marginally understood. Recently, activating FGFR3 mutations in the epidermis were shown to be involved in the development of seborrheic keratoses. 5 Transgenic mice expressing the S249C FGFR3 mutation in the basal layer of the epidermis under the control of the keratin 5 promoter developed thickening of the skin and verrucous skin tumors

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“…More recent studies using a rat bladder carcinoma model have shown that cells transfected with FGF1 are more tumorigenic and cells transfected with either FGF1 or FGF2 produced more vascularized tumours (Jouan- (Marsch et al, 1999). Several tumourderived cell lines have been shown to have high FGFR3 expression (Chandler et al, 1999) and overexpression of FGFR3 has been shown to promote overgrowth of con¯uent thyroid carcinoma cell lines (Onose et al, 1999). In addition, chimeric receptors possessing a highly activated form of the Fgfr3 tyrosine kinase domain can morphologically transform ®broblasts (Webster and Donoghue, 1997).…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma

2001

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4p16.3 has previously been identi®ed as a region of nonrandom LOH in transitional cell carcinoma, suggesting the presence of a tumour suppressor gene. One candidate within this region is ®broblast growth factor receptor 3 (FGFR3). Germline mutations in FGFR3 are known to cause several autosomal dominant skeletal dysplasias, the severity of which depends on the position and nature of the mutation in the protein. We investigated the frequency and nature of FGFR3 mutations in a panel of transitional cell carcinomas and cell lines and studied the possible link between mutation and loss of heterozygosity (LOH) on 4p16.3. FGFR3 coding sequence from 63 transitional cell carcinomas (TCC) of various stages and grades, and 18 cell lines was analysed by¯uorescent SSCP. Samples with abnormal migration patterns were sequenced to identify the mutation or polymorphism. Thirty-one of the 63 tumours had previously been assessed to have LOH at 4p16.3. Twenty-six of the 63 tumours (41%) and 4/18 (22%) of the cell lines had missense mutations in FGFR3. All mutations detected in our panel have been reported in the germline where all apart from one cause lethal conditions. One tumour contained K652Q which has recently been identi®ed in less severe cases of skeletal dysplasia. Tumours with and without LOH at 4p16.3 had mutations in FGFR3 suggesting that these two events are not causally linked. The frequency of FGFR3 mutation indicates that this protein plays an important role in TCC. Oncogene (2001) 20, 686 ± 691.

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Overexpression of fibroblast growth factor receptor 3 in a human thyroid carcinoma cell line results in overgrowth of the confluent cultures

Cited by 27 publications

References 27 publications

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization

Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma

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