Role of fibroblast growth factor receptor 4 in cancer

Fibroblast growth factor receptors (FGFR) play a significant role in both embryonic development and in adults. Upon binding with ligands, FGFR signaling is activated and triggers various downstream signal cascades that are implicated in diverse biological processes. Aberrant regulations of FGFR signaling are detected in numerous cancers. Although FGFR4 was discovered later than other FGFR, information on the involvement of FGFR4 in cancers has significantly increased in recent years. In this review, the recent findings in FGFR4 structure, signaling transduction, physiological function, aberrant regulations, and effects in cancers as well as its potential applications as an anticancer therapeutic target are summarized.     

Hormone refractory prostate cancer and fibroblast growth factor receptor

In prostate cancer, a distinct series of alterations in the fibroblast growth factor (FGF) family occurs during the progression from a hormone-dependent to independent state that disrupts communication between stroma and epithelium and results in autonomy of cancer cells. Changes include (i) loss of FGFR2lllb, which binds stromal-derived FGF-7, which promotes growth, growth limitation and differentiation and (ii) activation of FGFR1, the expression of which is normally limited to stroma, along with activation of FGFs that act on FGFR1 in an autocrine manner. Transfection of the FGFR2lllb isoform into hormone-independent prostate cancer cells not only causes growth inhibition, but also induces differentiation. However, introduction of FGFR1 by transfection in hormone-dependent prostate cancer cells accelerates their progression to malignancy. These results suggest distinct targets for therapy aimed at both inhibition of the malignant phenotype and restoration of homeostasis.     

Basic fibroblast growth factor in human prostate cancer cells.

To increase our understanding of the potential role of basic fibroblast growth factor (bFGF) in malignant progression of prostate cancer, we determined the production of bFGF, the expression of FGF receptor (flg), and the response to exogenous bFGF in LNCaP, DU 145, and PC 3 cells. We observed that these three prostate cancer cell lines, which differed in their dependence on androgens for growth in vitro and in their in vivo behavior in nude mice, could be distinguished as follows: (a) androgen-sensitive LNCaP cells, which do not metastasize in nude mice, did not produce measurable amounts of bFGF, expressed small but measurable amounts of FGF receptor mRNA, and did respond to exogeneous bFGF; (b) androgen-insensitive, moderately metastatic DU 145 cells did produce measurable amounts of biologically active bFGF, expressed large amounts of FGF receptor mRNA, and responded to exogeneous bFGF and the heparin-binding fractions from DU 145 cell extracts; (c) androgen-insensitive and highly metastatic PC3 cells also produced measurable amounts of bFGF but did not demonstrate a growth response to either the heparin-binding fractions from PC3 cell extracts or exogenous bFGF, even though large amounts of FGF receptor mRNA were expressed in PC 3 cells. These results suggest the possibility that differences in production of, and response to, bFGF may be associated with different biological behavior.     

Targeting fibroblast growth factor receptor signaling in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the primary type of liver cancer, and both the age-adjusted incidence and mortality of HCC have steadily increased in recent years. Advanced HCC is associated with a very poor survival rate. Despite accumulating data regarding the risk factors for HCC, the mechanisms that contribute to HCC tumorigenesis remain poorly understood. Signaling through the fibroblast growth factor (FGF) family is involved in fibrosis and its progression to cirrhosis of the liver, which is a risk factor for the development of HCC. Furthermore, several alterations in FGF/FGF receptor (FGFR) signaling correlate with the outcomes of HCC patients, suggesting that signaling through this family of proteins contributes to the development or progression of HCC tumors. Currently, there are no established systemic treatments for patients with advanced HCC in whom sorafenib treatment has failed or who were unable to tolerate it. Recently, several multikinase inhibitors that target FGFRs have demonstrated some early evidence of antitumor activity in phase I/II trials. Therefore, this review discusses the molecular implications of FGFR-mediated signaling in HCC and summarizes the clinical evidence for novel FGFR-targeted therapies for HCC currently being studied in clinical trials.     

Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells

Insulin-like growth factor 1 receptor (IGF-1R) activation is required for prostate cell proliferation. Prostate cancer is one of the most commonly diagnosed malignant tumors in Western countries. Overexpression of IGF-1R in prostate cancer is associated with tumor growth. These suggest that IGF-1R inhibitory agents may be of preventive and/or therapeutic value. With evidence accumulating for a chemopreventive role of flavonoids, the effects of luteolin, a bioactive flavonoid, on IGF-1R signaling in prostate cancer cells were examined. Luteolin inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells. Inhibition of AKT by luteolin resulted in decreased phosphorylation of its downstream targets, including p70S6K1, GSK-3beta and FKHR/FKHRL1. Luteolin also inhibited the IGF-1-induced activation of EGFR and MAPK/ERK signaling. Luteolin inhibited expression of cyclin D1 and increased expression of p21. As a result, luteolin suppressed proliferation and induced apoptosis of prostate cancer cells. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of prostate cancer cells. Results of in vivo tumor growth assay indicated that luteolin inhibited PC-3 tumor growth. Immunoblotting of the extracts of tumor tissues showed that luteolin inhibited IGF-1R/AKT signaling. Our results provide a new insight into the mechanisms that luteolin is against cancer cells.     

肿瘤治疗新靶点:碱性成纤维细胞生长因子及其受体信号

碱性成纤维细胞生长因子（bFGF）是一个促细胞分裂、增殖及血管生成的多肽生长因子,肿瘤组织中bFGF及其受体过度表达为抗肿瘤治疗提供潜在靶目标,研制靶向性抗bFGF抗体、FGFR抑制剂等抑制肿瘤细胞增殖和新血管形成,阻断肿瘤生长的营养和转移途径,成为抗肿瘤热点。本文就bFGF及其受体信号在肿瘤的发生、发展和转移中的作用及临床转化研究进行综述。      

Luteinizing hormone-releasing hormone agonist limits DU-145 prostate cancer growth by attenuating epidermal growth factor receptor signaling.

PURPOSE: Advanced prostate cancer is treated initially by central suppression of androgen production by luteinizing hormone-releasing hormone (LHRH) agonists. Intriguingly, even hormone-independent cancers often show some, if only slight, growth retardation when these agonists are delivered in pharmacological doses. Previous studies have shown in cell lines and animal xenograft models that activation of peripheral LHRH receptors on prostate carcinoma cells lead to growth suppression. In parallel, there is a decrease of epidermal growth factor receptors (EGFRs) and activity. Because autocrine EGFR stimulation exists in most, if not all, prostate carcinomas and is required for cell proliferation, we asked whether LHRH signaling cross-attenuated EGFR to limit tumor growth. One possible mechanism was suggested by LHRH receptors triggering phospholipase-C (PLC) to activate protein kinase C (PKC) because PKC activation limits EGFR tyrosine kinase activity by phosphorylating EGFR at threonine 654. EXPERIMENTAL DESIGN: To determine the role of this cross-attenuation mechanism, we mutated the threonine 654 amino acid to an alanine (A654) to abrogate this inhibition. DU-145 cells stably expressing wild-type and A654 EGFR were grown as xenografts in the s.c. space of athymic mice. RESULTS: DU-145 cells, overexpressing wild-type EGFR, formed tumors in athymic mice that were inhibitable by goserelin acetate (Zoladex). Tumors expressing the A654 EGFR were resistant to this growth inhibition. These results paralleled in vitro studies in which goserelin acetate blocked proliferation of the WT DU-145 but not A654 DU-145 cells. CONCLUSIONS: These data support the model of LHRH agonists preventing EGFR-mediated tumor growth through a PKC pathway. This suggests new targets of modulatory intervention to limit the growth of androgen-independent prostate carcinomas.     

A rare premalignant prostate tumor epithelial cell syndecan-1 forms a fibroblast growth factor-binding complex with progression-promoting ectopic fibroblast growth factor receptor 1.

The abnormal appearance and age-dependent loss of resident fibroblast growth factor receptor-2 (FGFR2) and gain of activity of FGFR1 in epithelial cells is a hallmark of the slow progression to malignancy in some models of prostate cancer. Pericellular matrix heparan sulfate (HS) is an integral subunit of the FGFR tyrosine kinase complex that restricts activity in absence of FGF, facilitates binding of an activating FGF, and confers specificity for FGF isoforms. In this report, we isolated and purified HS proteoglycan (HSPG) from premalignant prostate tumor epithelial cells based on the ability of the HS chains to form a binary complex with immunoglobulin module II of the ectopic and progression-promoting FGFR1 that was competent to bind FGF. The FGFR1 affinity-purified product exhibited a specific activity of over 600 times that of crude cellular HSPG enriched from cell lysates by ion exchange chromatography. The purified preparation exhibited a single NH(2)-terminal sequence with 11 of 13 residues identical to syndecan-1. The activity of purified recombinant glutathione S-transferase-tagged syndecan-1 expressed in premalignant epithelial cells confirmed that syndecan-1 bears HS chains that exhibit the rare motif that forms the FGF-binding complex with ectopic FGFR1. These results are the first to identify by affinity purification a specific HSPG core protein, the HS chains of which act as an integral subunit of the FGFR complex. The results suggest that syndecan-1 provides HS chains in premalignant epithelial cells to both the FGFR2- and FGFR1-signaling complexes that are integral to their dual roles in progression to malignancy.     

Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway

Dipeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinase-type plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway.     

Racial disparity of epidermal growth factor receptor expression in prostate cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors. PATIENTS AND METHODS: We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically. RESULTS: EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION: Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.     

Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth

Fibroblast growth factor receptors (FGFR) play important roles in many biological processes. Nothing is presently known about possible roles of the human FGFR1-IIIb mRNA splice variant. In this study, we characterized for the first time the effects of FGFR1-IIIb expression on the transformed phenotype of human pancreatic cancer cells. The full-length FGFR1-IIIb cDNA was generated and stably expressed in PANC-1 and MIA PaCa-2 pancreatic cancer and TAKA-1 pancreatic ductal cells. FGFR1-IIIb-expressing cells synthesized a glycosylated 110-kDa protein enhancing tyrosine phosphorylation of FGFR substrate-2 on FGF-1 stimulation. The basal anchorage-dependent and anchorage-independent cell growth was significantly inhibited. These effects were associated with a marked reduction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in combination with enhanced activity of p38 MAPK and c-Jun NH(2)-terminal kinase. FGFR1-IIIb expression inhibited single-cell movement and in vitro invasion as determined by time-lapse microscopy and Boyden chamber assay as well as in vivo tumor formation and growth in nude mice. Microscopic analysis of the xenograft tumors revealed a reduced Ki-67 labeling and a lower amount of tumor necrosis in FGFR1-IIIb-expressing tumors. Our results show that FGFR1-IIIb is a functional FGFR that inhibits the transformed phenotype of human pancreatic cancer cells.     

Androgen receptor signaling in androgen-refractory prostate cancer.

Prostate cancer is the second most prevalent cancer in males in the United States. Standard therapy relies on removing, or blocking the actions of, androgens. In most cases, this therapy results in a regression of the cancer because the prostate and most primary prostate tumors depend on androgens for growth and the avoidance of apoptosis. However, a portion of the cancers eventually relapse, at which point they are termed "androgen refractory" and can no longer be cured by conventional therapy of any type. The precise molecular events that lead from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are, therefore, of great interest. This review seeks to identify specific molecular events that may be linked directly to the progression to androgen-refractory cancer. Some of the mechanisms appear to involve the androgen receptor (AR) directly and include mutations in, or amplification of, the AR gene in a manner that allows the AR to respond to low doses of androgens, other steroids, or antiandrogens. In a less direct manner, coactivators may increase the sensitivity of the AR to androgens and even other nonandrogenic substances through a number of mechanisms. Additional indirect mechanisms that do not result from mutation of the AR may involve activation of the AR by peptide growth factors or cytokines or may involve bypassing the AR entirely via other cellular pathways. Identification of the role of these mechanisms in the progression to androgen-refractory prostate cancer is critical for developing therapies capable of curing this disease.     

成纤维细胞生长因子受体3在乳腺癌中的研究进展

成纤维细胞生长因子受体3（FGFR3）在调节细胞的增殖、分化及血管形成中发挥重要作用。近年来,研究发现 FGFR3在乳腺癌发生发展和内分泌治疗耐药性乳腺癌中发挥一定的作用,并且与乳腺癌患者的预后密切相关。     

Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling

The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor tyrosine kinase inhibitor with known FGFR/VEGFR activity, PD173074, showed reproducible growth inhibition. Possible mechanisms of growth suppression by PD173074 were implicated by reduced phosphorylation of AKT and MAPK, known oncogenic signal transducers. Subsequent reduction in the cyclin D1, cyclin D2 and CDK4 cell cycle regulators was also observed. Our results indicate that FGF signaling pathway inhibition as a monotherapy will slow, but not arrest growth of glioblastoma cells.     

Role of epidermal growth factor receptor in breast cancer

Decades of research in molecular oncology have brought about promising new therapies which are designed to target specific molecules which promote tumor growth and survival. The epidermal growth factor receptor (EGFR) is one of the first identified important targets of these novel antitumor agents. Approximately half of cases of triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) overexpress EGFR. Thus, EGFR inhibitors for treatment of breast cancer have been evaluated in several studies. However, results so far have been disappointing. One of the reasons for these unexpected results is the lack of biomarkers for predicting which patients are most likely to respond to EGFR inhibitors. Recent studies have shown that EGFR and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion and that high EGFR expression is an independent predictor of poor prognosis in IBC. Further, recent studies have shown that targeting EGFR enhances the chemosensitivity of TNBC cells by rewiring apoptotic signaling networks in TNBC. These studies indicate that EGFR-targeted therapy might have a promising role in TNBC and IBC. Further studies of the role of EGFR in TNBC and IBC are needed to better understand the best way to use EGFR-targeted therapy??e.g., as a chemosensitizer or to prevent metastases??to treat these aggressive diseases.