Fibroblast growth factor receptor 2, gain-of-function mutations, and tumourigenesis: investigating a potential link

Activating germline mutations in the fibroblast growth factor receptor (FGFR) gene family have been identified in several dominantly inherited skeletal disorders; in the case of FGFR3, the same somatically arising mutations have also been isolated from a variety of tumour tissues. Whilst the role of FGFR2 mutations in congenital syndromes has been well documented, their relationship with cancer has not been clearly defined. Based on evidence that gain-of-function mutations in FGFR2 drive positive selection in adult spermatogonia, the present study investigated, by denaturing high-performance liquid chromatography (DHPLC), DNA sequencing, and restriction digestion, the prevalence of FGFR2 mutations in 58 tumour cell lines of various types, and 29 testicular germ cell tumour samples. Although sequence variations and allelic imbalance were identified in FGFR2, none of the previously documented dominant mutations was detected in any of the tumour types examined. This suggests that gain-of-function FGFR2 mutations are not commonly encountered in tumourigenesis and specifically excludes a major contribution in testicular tumours.     

人成纤维细胞生长因子受体2的研究进展

人成纤维细胞生长因子受体2(fibroblast growth factor receptor 2,FGFR2)属于人类FGFR家族。FGFR2在骨骼发育、腺体发育、肢体形成、皮肤形成及多种器官的形成中发挥重要的作用。该文就FGFR2的结构、功能、所参与的细胞信号转导通路、相关疾病及其抑制剂的研发与应用作一综述。     

骨细胞形成过程中成纤维细胞生长因子受体3的调节作用及机制

文题释义： 失神经骨折：机体骨折合并有各类、各层面神经的损伤。随着社会经济的飞速发展,这类骨折的发生也逐年增多,在愈合过程中表现出较单纯骨折愈合加速且骨痂过量生长,甚至在肌肉中出现异位骨化,尤其是关节周围的骨折,严重影响关节功能和治疗效果,已成为修复重建和组织工程领域的研究热点。 创伤性神经损伤：包括创伤性颅脑损伤、脊髓损伤和周围神经损伤。这类损伤伴有骨折的患者表现出较单纯骨折愈合加速且骨痂过量生长,甚至在肌肉中出现异位骨化。 背景：在临床治疗中,创伤性神经损伤伴有骨折的患者表现出较单纯骨折愈合加速且骨痂过量生长,甚至在肌肉中出现异位骨化,严重影响这类骨折的治疗效果。对于影响失神经后骨折愈合加速的具体原因和机制,目前并不清楚。 目的：探索成纤维细胞生长因子受体3抑制剂在骨折愈合过程中的作用及表达变化规律。 方法：实验方案经兰州大学第二医院动物实验伦理委员会批准。选用60只雌性SD大鼠,制作坐骨神经损伤的胫骨横行骨折模型,随机分为实验组及对照组2组。实验组造模后腹腔注射成纤维细胞生长因子受体3阻滞剂;对照组造模后给等剂量生理盐水。分别于造模后4,7,10,14,21 d拍X射线片后取胫骨大体标本(每个时间点6只),取胫骨进行苏木精-伊红染色、Masson三色法染色组织学观察;计算大鼠胫骨骨细胞密度和骨小梁密度;测定胫骨组织纤维率。 结果与结论：①两组大鼠胫骨X射线观察差别不显著;②苏木精-伊红染色、Masson三色法染色结果显示实验组修复效果比对照组较好;③2组大鼠胫骨骨细胞密度、骨小梁密度及胫骨组织纤维率在7-14 d有明显差别(实验组>对照组);④抑制成纤维细胞生长因子受体3在周围神经失神经情况下能够加快骨折愈合,促进骨痂的塑形。成纤维细胞生长因子受体3在骨折后7-14 d时间段表达最为活跃。 ORCID: 0000-0002-7687-4383(许少策) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.     

Human epidermal growth factor receptor 2 expression in urothelial carcinoma of the renal pelvis: correlation with clinicopathologic parameters

The significance of human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is well established, and these patients are subsequently treated with Trastuzumab. Although HER2 expression in urothelial carcinoma of the urinary bladder has also been recently characterized, it has not been well studied in urothelial carcinoma of the renal pelvis. We investigated the relationship between HER2 overexpression in urothelial carcinoma of the renal pelvis and clinicopathologic parameters. Forty six cases were identified. HER2 overexpression was present in 34/46 (74%) cases. Mean patient age with HER2 overexpression was 68 years (range: 42-87 years). There was a male predominance with 28/34 (82%) patients. High grade urothelial carcinoma was present in 32/34 (94%) cases and 2/34 (6%) cases had low grade urothelial carcinoma. Pathologic staging was as follows; 9/34 (26%) cases were pTa, 10/34 (29%) cases were pT1, 2/34 (6%) cases were pT2, 12/34 (35%) cases were pT3, and 1/34 (3%) cases was pT4. An inverted growth pattern was present in 23/46 (50%) cases. HER2 overexpression was present in 15/23 (65%) cases of urothelial carcinoma with an inverted growth pattern. Our study showed that HER2 overexpression is more common in male patients with high grade urothelial carcinoma, especially those with an inverted growth pattern. It is highly conceivable that patients with urothelial carcinoma of the renal pelvis may be further stratified based on HER2 overexpression, and may also be potential candidates for Trastuzumab therapy in the neoadjuvant or adjuvant setting.     

I型成纤维细胞生长因子受体基因在肿瘤组织中的异常变化

成纤维细胞生长因子受体（ＦＧＦＲ） 包括４ 种类型。它们都是免疫球蛋白基因超家族的成员, 同时又是受体酪氨酸激酶, 可参与胚胎发育、损伤修复、血管发生和神经再生等多种重要的生理和病理生理过程。本实验对人胚胎和多种癌组织中的Ｉ型成纤维细胞生长因子受体（ＦＧＦＲ１） 基因组ＤＮＡ 进行了Ｓｏｕｔｈｅｒｎ 印迹分析,发现多种肿瘤的ＦＧＦＲ１ 基因组ＤＮＡ的杂交结果不同, 而与胚胎期ＦＧＦＲ１ 基因组ＤＮＡ 的杂交结果相似。以上结果提示, 恶性肿瘤细胞似乎获得了胚胎细胞的某些特点, 具有超常生长增殖的能力; 肿瘤细胞中的ＦＧＦＲ１ 可能也有胚胎化倾向, 从而使ＦＧＦＦＧＦＲ 系统在肿瘤的发生、发展中发挥异常功能。     

多形性胶质母细胞瘤中表皮生长因子受体的研究进展

表皮生长因子受体（ epidermal growth factor receptor ， EGFR ）是一种重要的跨膜受体，与细胞增殖、分化、凋亡密切相关。在多形性胶质母细胞瘤（ glioblastoma multiforme ， GBM ）中， EGFR 普遍高扩增高表达，且在部分 GBM 样本中以双微体（ double minute chromosomes ， DMs ）的形式存在，对 GBM 的发生发展，以及不良预后起着重要作用。本文简述了 EGFR 的功能，其与 GBM 的关系及其靶向治疗药物。     

Promotion of neurite outgrowth by fibroblast growth factor receptor 1 overexpression and lysosomal inhibition of receptor degradation in pheochromocytoma cells and adult sensory neurons

Basic fibroblast growth factor (FGF-2) is up-regulated in response to a nerve lesion and promotes axonal regeneration by activation of the tyrosine kinase receptor fibroblast growth factor receptor 1 (FGFR1). To determine the effects of elevated FGFR1 levels on neurite outgrowth, overexpression was combined with lysosomal inhibition of receptor degradation. In pheochromocytoma (PC12) cells, FGFR1 overexpression resulted in flattened morphology, increased neurite outgrowth and activation of extracellular signal-regulated kinase (ERK) and AKT. Degradation of FGFR1 was inhibited by the lysosomal inhibitor leupeptin and by the proteasomal inhibitor lactacystin. In rat primary adult neurons, FGFR1 overexpression enhanced FGF-2-induced axon growth which was further increased by co-treatment with leupeptin. Lysosomal inhibition of receptor degradation concomitant with ligand stimulation of neurons overexpressing FGFR1 provides new insight in tyrosine kinase receptor-mediated promotion of axon regeneration and demonstrates that adult sensory neurons express sub-optimal levels of tyrosine kinase receptors for neurotrophic factors.     

Human epithelial growth factor receptor 2 (HER2) status in primary and metastatic esophagogastric junction adenocarcinomas

Differences in human epithelial growth factor receptor 2 dysregulation in primary solid tumors and metastases may (at least partially) explain human epithelial growth factor receptor 2-targeted therapeutic inconsistencies. Human epithelial growth factor receptor 2 status was tested in a series of 47 radically treated consecutive esophagogastric junction adenocarcinomas (male/female, 38/9; mean age, 67.9 years) in both primary cancers and paired synchronous nodal metastases. None of the patients received neoadjuvant therapy. For each case, 2 nonadjacent tissue samples from primary esophagogastric junction adenocarcinoma and 2 different metastatic nodes were considered (188 tissue samples in all). Human epithelial growth factor receptor 2 status was assessed by immunohistochemistry (PATHWAY-HER2/neu [4B5]; Ventana Medical Systems, Milan, Italy) and dual chromogenic in situ hybridization (duoCISH; DAKO, Glostrup, Denmark). Immunohistochemistry staining scores were nil in 22 tumors (47%), 1 (21%) in 10, 2 (13%) in 6, and 3 (19%) in 9. Human epithelial growth factor receptor 2 gene amplification (25.5%) was associated with more differentiated phenotype (Fisher exact test, P = .039) and advanced tumor stage (Fisher exact test, P = .015). Significant agreement was observed between human epithelial growth factor receptor 2 protein expression (immunohistochemistry) and human epithelial growth factor receptor 2 gene's amplification (chromogenic in situ hybridization) (κ = 0.84, P < .001). Both immunohistochemistry and chromogenic in situ hybridization documented an excellent intratumor agreement in human epithelial growth factor receptor 2 status (κ = 0.75, P < .001; κ = 0.88, P < .001, respectively). Human epithelial growth factor receptor 2 status was comparable in primary versus metastatic nodal cancers by both immunohistochemistry and chromogenic in situ hybridization (Cohen Φ, both P < .001). In esophagogastric junction adenocarcinomas, human epithelial growth factor receptor 2 status (as assessed by immunohistochemistry and/or chromogenic in situ hybridization) is virtually unaffected by intratumor variability; it is consistent with findings in nodal metastases, and it reliably identifies patients with esophagogastric junction adenocarcinoma eligible for anti-human epithelial growth factor receptor 2 therapy.     

Clinical evaluation of colony-stimulating factor 1 receptor inhibitors

Signaling through colony-stimulating factor 1 receptor (CSF1R) regulates the development, differentiation, and activation of mononuclear phagocytic cells. Inhibition of this pathway provides an opportunity for therapeutic intervention in diseases in which these cells play a pathogenic role, including cancers, inflammation, fibrosis, and others. Multiple monoclonal antibodies and small molecule inhibitors targeting CSF1R or its known ligands CSF1 and IL-34 have been clinically tested and are generally well tolerated with side effects associated with on-target macrophage inhibition or depletion. To date, clinical activity of CSF1R inhibitors has been primarily observed in diffuse-type tenosynovial giant cell tumors, a disease characterized by genetic alterations in CSF1 leading to dysregulated CSF1R signaling. Expanded development into novel indications such as chronic graft vs host disease may provide new opportunities to further explore areas where a role for CSF1R dependent monocytes and macrophages has been established. This review presents key findings from the clinical development of 12 CSF1/CSF1R targeted therapies as monotherapy or in combination with immune checkpoint inhibitors and chemotherapy.     

Human epidermal growth factor receptor 2 (HER2) immunoreactivity: specificity of three pharmacodiagnostic antibodies

Schrohl A‐S, Pedersen H C, Jensen S S, Nielsen S L & Brünner N
(2011) Histopathology 59 , 975–983 Human epidermal growth factor receptor 2 (HER2) immunoreactivity: specificity of three pharmacodiagnostic antibodies Aims: The availability of specific antibody‐based test systems is essential to testing of HER2 protein expression. Here, we mapped epitopes recognized by three pharmacodiagnostic HER2 antibodies and investigated their specificity towards peptides and fusion proteins homologous to the intracellular domains of HER1, HER2, HER3 and HER4. The investigated antibodies were PATHWAY^® HER2 (clone 4B5; Ventana Medical Systems Inc., Tucson, AZ, USA), HercepTest? (Dako Denmark A/S, Glostrup, Denmark), and Oracle^® HER2 (clone CB11; Leica Microsystems GmbH, Wetzlar, Germany). Methods and results: Epitopes were mapped using the alanine scanning method. Specificity was investigated in immunohistochemical stainings, competitive enzyme‐linked immunosorbent assay (ELISA) and immunoblotting. All three antibodies reacted with HER2 proteins and peptides in immunohistochemical stainings, ELISA and immunoblotting. PATHWAY^® HER2 also stained HER4‐expressing cells, reacted with HER4 peptide in ELISA and detected HER4 fusion protein in an immunoblot. Oracle^® HER2 weakly detected HER4 in immunohistochemical stainings, whereas the HercepTest? antibody showed no cross‐reactivity with other HER proteins. Conclusion: Our study shows that the PATHWAY^® HER2 antibody can bind HER4 peptides and fusion proteins in three different experimental settings. This should be investigated further to determine whether binding of HER4 also occurs in tissue samples and if such binding would have implications for therapy decisions for breast cancer patients.     

Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats

 This study aimed to examine the influence of acute tissue hypo-oxygenation on the expression of the vascular endothelial growth factor (VEGF) receptor genes. To this end male Sprague-Dawley rats were exposed to different hypoxic conditions such as 10% or 8% oxygen, 0.1% carbon monoxide and cobalt chloride (60 mg/kg) for 6 h and the abundance of flt-1, flt-4 and flk-1 mRNA in lungs and livers was determined by RNase protection assay. The relative proportions of flt-1, flt-4 and flk-1 were 10 : 2.5 : 1 and 10 : 10 : 2 in normoxic lungs and livers, respectively. It was found that 8% but not 10% oxygen increased flt-1 mRNA two- to threefold in both organs, whilst flt-4 and flk-1 mRNA were not changed by acute inspiratory hypoxia. Carbon monoxide inhalation also increased flt-1 mRNA but not flt-4 or flk-1 mRNA in both organs. Subcutaneous cobalt administration increased flt-1 mRNA in the livers only, whilst flt-4 and flk-1 mRNA remained unchanged. These findings show that acute tissue hypo-oxygenation is a rather selective stimulus for flt-1 gene expression. The efficiency of the different manoeuvres applied to stimulate flt-1 gene expression is rather similar to the stimulation of erythropoietin gene expression. It is not unreasonable to assume, therefore, that the oxygen-dependent regulation of both genes at the cellular level has significant similarities.     

Changes of type I fibroblast growth factor receptor gene during development

目的研究人成纤维细胞生长因子受体1(FGFR1)基因在发育过程中的可能变化。方法采用Southernblot的方法对胎儿及多种组织基因组DNA进行分析。结果成人FGFR1基因与胚胎期的在基因组水平上是不同的。结论人FGFR1基因在发育过程中可能发生了重排或丢失,这种变化可能导致FGFR1在胚胎期和成年期的表达水平和分子结构的不同,从而改变细胞的功能状态。     

Clinical spectrum of fibroblast growth factor receptor mutations

During the last few years, it has been demonstrated that some syndromic craniosynostosis and short‐limb dwarfism syndromes, a heterogeneous group comprising of 11 distinct clinical entities, are caused by mutations in one of three fibroblast growth factor receptor genes (FGFR1, FGFR2, and FGFR3). The present review list all mutations described to date in these three genes and the phenotypes associated with them. In addition, the tentative phenotype‐genotype correlation is discussed, including the most suggested causative mechanisms for these conditions. Hum Mutat 14:115–125, 1999. © 1999 Wiley‐Liss, Inc.     

HER2在上皮性卵巢癌中的研究进展

HER2是原癌基因HER2/neu编码的跨膜糖蛋白,可以通过IHC、FISH和分子影像等方法测定。这种癌基因在不同组织学分型和临床分期的上皮性卵巢癌中的表达对预后和治疗靶值的临床应用已被广泛研究,但是目前尚无一致意见。近期的文献中表明HER2过度表达与低分化晚期肿瘤及化疗耐药和生存期缩短有关。对于晚期卵巢癌患者,最初先行减压手术和紫杉醇、铂类药物组合的标准治疗,但后来发展为化疗耐药性疾病,因此需要更多的治疗方法来提高患者生存率。近年来针对HER2的靶向治疗成为临床研究的热点。     

The first Korean case of Beare-Stevenson syndrome with a Tyr375Cys mutation in the fibroblast growth factor receptor 2 gene

Here we report the first case of a Korean infant with a cloverleaf-shaped craniosynostosis, in which the diagnosis of Beare-Stevenson syndrome was suspected upon observation of the typical morphological features. This infant exhibited craniofacial anomalies, ocular proptosis, cutis gyrata, acanthosis nigricans, prominent umbilical stump, furrowed palms and soles, hypospadia, and sacral skin tag coupled with dermal sinus tract. Brain magnetic resonance imaging revealed that the patient also had non-communicating hydrocephalus with Chiari malformation. This is the 8th report of Beare-Stevenson syndrome in the literature, which was confirmed by the detection of a Tyr375Cys mutation in the fibroblast growth factor receptor 2 (FGFR2) gene.