Skip to main content

Role of tyrosine kinases in bladder cancer progression: an overview

Abstract

Background

Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. Since, majority of BCa cases are diagnosed after macroscopic clinical symptoms, it is required to find efficient markers for the early detection. Receptor tyrosine-kinases (RTKs) and non-receptor tyrosine-kinases (nRTKs) have pivotal roles in various cellular processes such as growth, migration, differentiation, and metabolism through different signaling pathways. Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies.

Main body

For the first time in present review we have summarized all of the reported tyrosine-kinases which have been significantly associated with the clinicopathological features of BCa patients.

Conclusions

This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis.

Video abstract

Background

Bladder cancer (BCa) is the 10th most frequent malignancy worldwide [1], and the fourth most prevalent malignancy among American males with 7% of all cancer cases [2]. There are an estimated 62,100 new BCa cases and 13,050 deaths annually among American males [2]. Approximately 430,000 new cases of BCa and 150,000 deaths were reported in 2012 worldwide [3]. The highest incidence rates were observed in both sexes in European countries and Northern America, while the Lebanese females had the highest rates in the world [1]. There is a correlation between age and higher risk of BCa progression [4]. The BCa is also three to four times more frequent among males compared with females [5]. The prevalence of BCa can be associated with environmental and genetic determinants, which are different among racial/ethnic groups [6, 7]. Based on histopathologic features of tumor cells, there are three main types of BCa including: transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma, which account for 90, 5%, and less than 2% of BCa cases, respectively [8]. Non-muscle-invasive bladder cancer (NMIBC) or superficial bladder cancer which constitutes about 75% of newly diagnosed cases is confined to the lamina propria without invasion to underlying muscle tissues. Muscle-invasive bladder cancer (MIBC) involves about 25% of cases that has invasion to the muscularis propria and perivesical fat [9]. There are various treatment options for the BCa including radical cystectomy, transurethral resection, chemotherapy, radiotherapy, immunotherapy, and targeted therapies against specific signaling proteins [10, 11]. Over the past decades, mutations in kinases have been shown to be engaged in bladder malignancies [12]. Protein kinases are a large family of proteins with more than 500 members which are encoded by ~ 2% of all human genome. Their main function is the phosphorylation of definite amino acids on key proteins involved in critical cellular mechanisms such as proliferation, differentiation, survival, and apoptosis [13, 14]. As these cellular processes are of paramount importance, the enzymatic function of these kinases is strictly regulated [15]. Tyrosine-kinases (TKs) are one of the major types of protein kinases which induce phosphorylation of tyrosine residues on a substrate protein. TKs are found in nuclear and membrane-bound forms as well as transmembrane receptors [16]. There are about ninety TKs in human genome which are involved in various cellular processes such as differentiation, metabolism, motility, and proliferation [17, 18]. Receptor tyrosine-kinases are up regulated in various tumors and are considered to be potential oncogenes involved in cancer initiation and development [19, 20]. Therefore, targeting these oncogenes and inhibiting their expression may result in good clinical outcomes [21]. The majority of TKs share a similar structure consisting of a conserved catalytic domain and regulatory domains which are located within or outside the catalytic domain. The catalytic domain contains 250–300 amino acids in 12 conserved subdomains and catalyzes the transfer of a phosphate group from ATP to the tyrosine residue. Activation and recruitment of downstream signaling pathways occur following this phosphorylation. Regulatory domains regulate the kinase activity and its localization in response to different stimuli [22, 23]. Studies have shown oncogenic characteristics of TKs [24]. Dysregulation of TKs by gain of function mutations or over expression occurs in various malignancies like BCa which accelerates tumor proliferation and progression [25, 26]. Therefore, inhibiting signaling pathways of different tyrosine kinases using tyrosine-kinase inhibitors (TKIs) have been reported as efficient method of tumor targeted therapies [27,28,29]. BCa patients are diagnosed with a broad range of tumor behaviors from low grade and stage tumors with less aggressiveness to tumors with advanced grade, stage, and distant metastasis. Clinicopathological features are commonly used to predict tumor growth, recurrence, and patient’s survival. However, the gene expression profiling and molecular pathway analysis have gained growing attention as a novel and promising methods for the prediction of disease course and prognosis in BCa patients [7, 30, 31]. Since, tyrosine-kinases have essential roles in BCa progression, in present review we have summarized all of the studies which have been assessed the role of tyrosine-kinases in BCa patients in the world (Table 1).

Table 1 All of the tyrosine kinases which have been significantly associated with clinicopathological features of BCa patients in the world

Main text

RTK class I

The ERBB family includes ERBB1 (EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4) that are the class I receptors of tyrosine-kinases (RTKs). The HER2/neu is involved in transduction of mitogen signals through activation of various signaling pathways such as MAP kinase, PI3 kinase, and MYC [104, 105]. The prevalence of HER2/neu over expression in BCa is one of the most elevated among human malignancies, with a range of 9 to 34% of examined cases [106, 107]. HER2 up regulation is mainly due to gene amplification which triggers intracellular pathways that promote cell proliferation, migration, and aggressiveness of tumor cells [105, 108]. Various studies have been reported that there were significant associations between tumor grade and HER-2 up regulation or gene amplification among different population of BCa patients [32,33,34,35,36]. The pT2 tumors have a considerable amount of mutations compared with pTa/Ti tumors [109]. Protein up regulation and gene amplification of HER2/neu occur more frequently in pT2 tumors in comparison with pTa/Ti tumors which are correlated with a poor prognosis [107, 110,111,112,113,114]. A significant high frequency of chromosome 17 polysomy (97%) and increased HER2/neu copy number (92%) were also observed in a sample of BCa patients. Polysomy 17 and HER2/neu up regulation were frequent in G3 pT2 tumors [37]. Another study has been shown that there was HER2/neu abnormality in pT2 BCa tumors before muscle invasion. Polysomy 17 and HER2/neu amplification and up regulation were correlated with advanced disease. Therefore, the HER2/neu deregulation was observed before the muscle invasion [38]. A quarter of patients experiencing cystectomy and lymphadenectomy for N0M0 staged BCa showed lymph node metastases which resulted in death among two thirds of patients [115, 116]. The chemotherapy is not efficient in metastasizing bladder malignancy, and new therapeutic modalities are required [117, 118]. It has been observed that the HER2 amplification was significantly increased in urothelial bladder tumors with lymph node metastasis compared with initial tumors. HER2 amplification was also significantly associated with poor prognosis [39]. Another study has been shown that the patients with distant metastasis had co amplifications of HER2 and MYC in a sample of BCa cases. There was also a significant correlation between HER2 or MYC amplification and high-stage (pT4) tumor [40]. It has been shown that there were significant increased levels of HER2/neu expression in a sample of malignant BCa patients compared with benign and healthy cases. There were significant correlations between HER2/neu, ploidy, SPF, and lymph node involvement [41].

About 75% of BCa patients have NMIBC that can be limited to the mucosa (Ta) or carcinoma in situ (Tis) without stromal invasion or submucosal invasion (T1). Unsaturated fat synthase (FASN) down regulation induces apoptosis and represses tumor progression and metastasis [119]. FASN can be phosphorylated by mTOR and HER2/neu which is associated with its function and cellular localization [120]. HER2/neu triggers PI3K/AKT and Ras/Raf/MAPK signaling pathways as the stimulators of FASN. It has been observed that there were significant correlations between FASN expression, tumor size, grade, recurrence, and stage. Moreover, there was a correlation between FASN and HER2/neu which had prognostic value among NMIBC patients. HER2/neu up regulated the FASN through PI3K and MAPK pathways. FASN and HER2/neu up regulations were associated with shorter RFS and poor PFS among NMIBC cases [42]. HER2 up regulation has been observed in a sample of NMIBC patients which was significantly correlated with advanced grade and stage, bigger size, and adjacent tissues invasion. HER2 positive patients had markedly lower progression-free survival in comparison with HER2 negative cases [43]. It has been reported that the over expression of ERBB2 was significantly correlated with high grade and advanced stage tumor among a group of NMIBC patients [44]. A significantly higher level of urinary HER2/neu was also observed among a sample of NMIBC patients compared with normal subjects. Moreover, HER2/neu level/urinary creatinine ratio was significantly associated with advanced tumor grade [45]. It has been reported that the patients with positive HER2 expression had significantly shorter disease-free survival compared with negative HER2 expression cases in a sample of MIBC patients. This difference was more significant in patients with advanced stage and grade who were candidates for adjuvant treatment. The HER2/neu expression was significantly associated with higher tumor grade and stage, and lymph nodes involvement. Moreover, patients with HER2 up regulation had a worse disease-specific survival compared with normal HER2 expressed patients [46]. It has been observed that the HER2 and NFkB up regulations had a key role in tumor cells resistance against chemotherapy among a sample of MIBC patients. HER2 and NFkB Over expressions were significantly correlated with poorer survival in chemotherapeutic–treated MIBC patients who were undergone cystectomy. High expression levels of NFkB were also significantly associated with drug resistance in MIBC patients. Therefore, HER2 and NFkB up regulations can be resulted in a worse prognosis in chemotherapeutic–treated MIBC patients who were undergone cystectomy [47]. Another study has been shown that there was a significant association between HER2 up regulation and CRT resistance. Targeting HER2 improves prognosis of MIBC cases that were treated with CRT-based bladder-sparing methods [48].

Upper urinary tract urothelial carcinoma (UUTUC) is an uncommon type with frequency of 5–10% among all urothelial carcinomas. It has been shown that there was significant association between HER2 protein up regulation, gene amplification, grade, and shorter recurrence period. HER2 positivity was more in patients over 70 years old compared with patients under 70 years old [49]. Plasmacytoid urothelial carcinoma is also another rare type of urothelial carcinoma that is distinguished by plasma-cell-like cancer cells [121, 122]. It has been reported that the plasmacytoid urothelial carcinoma patients had HER2 protein up regulation and gene amplification [50]. Heregulin (HRG) is ligand of ERBB family of receptors that can regulate cell proliferation, apoptosis, and differentiation [123,124,125]. It has been reported that the HER3 and HER4 up regulations and their initiating ligands are correlated with good prognosis among BCa patients. Patients with high HER3 and HER4 expressions had increased survival rate. There was significant HRG2b loss in invasive tumors in comparison with non-invasive tumors. Moreover, there was a significant association between (HER3 and HER4) and (HRG2 and HRG4) expressions [51]. It has been show that there were significant different levels of ErbB4 protein expressions between a sample of bladder tumors and normal margins. EGFR and HER2 were down regulated and up regulated respectively in tumor tissues in comparison with non-malignant bladder tissues [52].

EGFR functions in a dimeric structure of different EGF receptors for the signal transduction [126, 127]. Dimeric pairs are related to the concentration of both receptors and specific ligands and also the affinities between receptors [128, 129]. It has been reported that there were associations between the elevated levels of growth factors and also their receptors and tumor recurrence in a sample of BCa patients. Tumor tissues had increased levels of EGFR and related growth factors at early stages [53]. Another study has been reported that there was EGFR up regulation in invasive BCa tumors. Progression free survival rate in patients without any progression were significantly lower among EGFR positive cases [54]. It has been reported that there were associations between EGFR expression, tumor grade, and stage [55, 56]. The increased EGFR levels of expressions were significantly associated with advanced stage and overall survival rates among muscle invasive bilharzial bladder cancer (MI-BBC) patients [57]. Another study has been shown that the EGFR up regulation was significantly correlated with aneuploidy and polysomy in a sample of BCa tumors. A significant association was also observed between high expression of EGFR and P53. Moreover, up regulation was positively associated with tumor invasiveness, aneuploidy, non-papillary type, and grade. Therefore, highly expressed EGFR is typically a delayed event during BCa progression due to genomic instability [58]. EGF and five other ligands capable of binding to EGFR are among the various family-specific EGF ligands, while heregulins are the HER3 and HER4 ligands [130]. The expression levels of HER1–4 were assessed in bladder tumors, which showed that the up regulation of HER3 and/or HER4 was a protective factor against the negative outcome of HER1 and/or HER2 over expression. Over expression of either HER1 or HER2 in HER3 and HER4 down regulated tumors were correlated with decreased survival. Therefore, HER1 and HER2 over expressions resulted in poor prognosis and tumor progression only if there were HER3 and HER4 under expressions. Patients with high expression levels of HER1 but HER3 and HER4 down regulations had a poorer prognosis than those with high levels of HER1, HER3, and HER4. Furthermore, patients expressing high levels of HER2 but HER3 and HER4 down regulations had a significantly lower survival rate compared with patients with up regulated HER2, HER3, and HER4 [59].

Radical cystectomy is the standard treatment option for MIBC, however about half of these cases had tumor metastasis during 2 years [131, 132]. Patients with metastatic BCa receive systemic Cisplatin-based therapy as the first-line treatment modality, which has a poor prognosis in advanced tumor stage [133, 134]. It has been reported that the EGFR up regulation was correlated with chemo resistance in a sample of BCa patients. The S100A9 and EGFR suppressions decreased tumor cells viability and Cisplatin-resistance. Moreover, the S100A9 and EGFR up regulations were observed in MIBC patients [60]. Another study has been reported that there was a significant correlation between EGFR negative tumor and positive radio therapeutic response at 3-month check cystoscopy. Lack of radiotherapy response at 3-month check cystoscopy was an autonomous prognostic indicator for the reduced survival rate of bladder malignancy. Positive EGFR status predicted future local relapse following a previous complete radio therapeutic response [61]. It has been shown that there was EGFR up regulation in muscle invasive in comparison with lower invasive bladder tumors which were also correlated with advanced tumor stage. EGFR and TGF-α co-expression was significantly correlated with muscle invasion [62]. The EGFR up regulation can predict a poor prognosis compared with lack of EGFR expression in a sub population of MIBC patients. There was also a significant association between EGFR over expression and tumor relapse after adjuvant chemotherapy for advanced BCa, which introduced EGFR as a useful prognostic marker of BCa [63]. It has been shown that some high-grade bladder tumor patients had increased urinary level of EGFR. EGFR levels in urine can be used as a predictor of survival [64]. The EGFR 3′UTR 774 T > C polymorphism can be associated with higher risk of BCa progression. Patients with EGFR 774CC genotype were significantly more susceptible to BCa in comparison with 774TT/TC genotype [65]. There was also a significant correlation regarding EGFR_03 and EGFR_05 variants with a higher risk of BCa progression, and EGFR_05 and EGFR_1808 variants with a prolonged survival. EGFR_03 and EGFR_05 polymorphisms were correlated with higher BCa risk. Patients with polymorphic EGFR alleles showed higher survival rate than patients with wild-type EGFR. However, mutated type of the EGF_04 ligand showed lower survival rate than wild-type [66].

Micropapillary urothelial carcinoma (MPUC) is an aggressive urothelial cancer with poor prognosis which is due to the high tendency of tumor for lymphovascular invasion. Majority of the MPUC patients have a high grade and stage tumor at the time of diagnosis [135]. It has been shown that there was a significant EGFR up regulation in a sample of MPUC patients [67]. Tumors with muscle invasion (stage T2-T4) showed a significant higher progression and metastasis, with decreased 5-year survival rates. Cell-to-cell and cell-to-matrix signals are mainly transmitted through tyrosine-kinases that results in alteration of cell differentiation, motility, attachment, and apoptosis [17]. It has been reported that there were HER2 and EGFR up regulations in a sample of BCa in comparison with typical urothelium. The HER2 and EGFR over expressions had an important role in the early stages of tumor progression. Moreover, there were significant correlations between HER2 expression and HER2 and EGFR coexpression in patients with T1 disease [68]. It has been reported that there was a significant association between nuclear positivity of c-MYC and HER2 up regulation among a group of transitional cell BCa patients. Cytoplasmic c-MYC expression was also correlated with grade, papillary status, and EGFR/HER2 up regulation [136]. EGFR- and/or HER2 up regulation has been also reported to have a significant association with higher frequency of recurrence in BCa patients [69]. It has been observed that there was a significant positive association between HER2 and EGFR expressions in a sub population of transitional BCa patients. Bladder tumor cells had significantly higher levels of EGFR and HER2 expressions compared with controls. Patients with advanced tumor grade and stage, and tumor relapse had significant increased expression of EGFR in comparison with patients with lower grade and stage of tumor, and lack of recurrence. Patients with advance stages and tumor relapse also showed increased levels of HER2 expression compared with recurrence free patients with lower tumor stages [70]. It has been shown that the EGFR up regulation and ErbB4 down regulation were significantly correlated with tumor aggressiveness, advance grade, and poor overall survival in a sub population of BCa patients. The patients with EGFR down regulation had higher recurrence-free survival in comparison with patients with EGFR up regulation. Patients without ErbB4 down regulation had better 5-year overall survival and were more likely to have small, low-grade, and non-invasive tumors [71].

RTK class II

Insulin-like growth factor-1 receptor (IGF1R) is belonged to the class II RTKs which have pivotal functions in regulation of cell proliferation, migration, apoptosis, and differentiation. IGF-IR has an anti-apoptotic function during tumor progression [137]. It has been shown that the IGF1R expression was correlated with the race and pT classification in malignant UC cases. There was a negative association between pT classification and IGF1R expression in which the IGF1R over expression was less in pT4 cases compared with lower pT categories. IGF1R over expression was significantly correlated with mortality which can be introduced as a prognostic factor of BCa [72]. Another study has been reported that there was significant IGF1R over expression in a sample of BCa tissues compared with healthy urothelium. Both invasive and superficial (Ta–T1) bladder tumors had higher expression levels of IGF1R compared with normal bladder tissue [73]. It has been observed that the IGF-IR promotes bladder tumor cells migration and invasion through AKT-ERK related activation of Paxillin. Since, phosphorylated Paxillin colocalizes with FAK in focal adhesion in migrating cells, Paxillin suppression reduced the invasion of 5637 and T24 cell lines. There was also IGF-IR up regulation in a sample of invasive BCa tissues compared with normal margins [74]. Decorin is belonged to the small leucine-rich proteoglycans involved in tumor progression via RTKs suppression [75, 138]. It has been shown that there were significant IGF-IR over expression in high grade in comparison with low grade BCa samples. There was also an inverse correlation between the levels of decorin and IGF-IR expressions in BCa. Moreover, Decorin suppressed tumor cell invasion through IGF-IR inhibition [139].

RTK class V

Basic Fibroblast Growth Factor (bFGF) is a cationic protein that binds with heparin and is involved in angiogenesis and tumor progression. The basic FGFR is belonged to the class V of RTKs, and syndecans are essential for its activation. Ligand binding causes FGFR dimerization, which leads to the kinase domain autophosphorylation and phosphorylation of effector signaling proteins. Syndecans binding with both bFGF and their FGFRs functions as stimulators while syndecans that bind only bFGF operate as signaling inhibitors. It has been shown that there were significant FGFRI, FGFR2, bFGF, and syndecan1–4 up regulations in a sample of BCa tissues [76]. Different changes and variations have been detected in the members of phosphatidylinositol 3-kinase (PI3K) pathway in urinary BCa [140, 141]. This pathway has key roles in regulation of cellular growth and survival [142]. It has been reported that the PIK3CA mutations and amplification were a preliminary and prevalent occurrence among NMIBC patients which were correlated with reduced tumor relapse. In low-grade tumors there was also a correlation between PIK3CA and FGFR3 mutations. Moreover, patients with wt PIK3CA and FGFR3 mutated tumors had significantly higher recurrence rates. An exceptionally high rate of PIK3CA mutations and gene amplifications were particularly found in T1 and T2 tumors. Mutations and amplifications in PIK3CA induced AKT function [77]. PI3K can be activated by FGFR or ERBB through the binding of RAS to PIK3CA. It has been shown that the majority of UCC cases had mutations in PIK3CA, FGFR3, HRAS, KRAS, BRAF, and AKT1 genes. Mutations were significantly more frequent in FGFR3, PIK3CA, and FGFR3. The frequencies of mutations were negatively associated with grade. FGFR3mut and FGFR3mut- PIK3CAmut genotypes were correlated with low grade tumors, while the KRASmut- PIK3CAmut- and AKT1mut were observed in high-grade tumors [78]. Another study has been shown that the majority of patients with low-grade NMI-BC had a mutation in KRAS, NRAS, HRAS, PIK3CA, and FGFR3 genes. Therefore, mutational analysis of these genes along with regular cystoscopic examinations can be an efficient method of following-up among patients with grade 1–2 NMI-BC [79]. It has been observed that there was significant correlations between mutated FGFR3 and lower tumor stage/grade [80]. BCa patients with mutated FGFR3 had higher rate of vascularization in comparison with wild-type FGFR3. FVIII up regulation was the only angiogenic factor associated with mutated FGFR3. The T1 MIBC patients with mutated FGFR3 had significantly higher risk of recurrence compared with wild-type FGFR3 carriers. FGFR3 was also a poor prognostic factor and promoted tumor angiogenesis. Therefore, FGFR3-targeted therapies can be effective in reducing tumor angiogenesis [81]. Most of bladder tumors (75–80%) are papillary noninvasive (pTa) or superficially invasive (pT1) urothelial tumors, whereas the others (20–25%) are muscle-invasive (pT2). FGFR3 mutations are more common in pTa bladder tumors [82, 143, 144], less regular in pT1G3 tumors [145, 146], and rare in carcinoma in situ (pTis) [82, 146]. The BCa patients with a FGFR3 mutation appeared to have a better outcome compared with mutation free patients [144]. It has been reported that the FGFR3 and CK20 were efficient prognostic factors of pTa bladder tumors, since it can distinguish the differentiated tumors with FGFR3 mutations. The FGFR3 mutation with a normal CK20 expression pattern was observed in low-grade non-invasive papillary tumors [83]. It has been observed that the FGFR3 mutations were significantly more common in pTa BCa tumors. The patients with mutant FGFR3 had significantly lower death rate. The FGFR3 mutations can precisely determine patients with invasive tumor who were at lower risk of progression. The carriers of FGFR3 mutations had better prognosis [84]. Another study has been shown that the prevalence of FGFR3 mutation was significantly higher in pTa tumors compared with carcinoma in situ (CIS), pT1, and pT2–4 among a sub population of BCa patients. There were also significant correlations between FGFR3 mutations and low grade tumors [82]. It has been reported that the FGFR3 up regulation was more common in well-differentiated in comparison with poorly-differentiated tumors and in low stage tumors in comparison with advance stage tumors among BCa patients. There were significant associations between loss of FGFR3, stage, and grade [85]. A negative association was also reported between the levels of FGFR3 expression and grade. There was also significant inverse correlation between CDKN2A/p16 and FGFR3 expressions. CDKN2A/p16 up regulation and FGFR3 down regulation were significantly associated with poor progression-free survival [86]. MAP kinase, STAT1, PI3K-AKT, and PLCγ are important signaling pathways to mediate the FGFR3 functions [147,148,149]. It has been shown that there was a declining trend of FGFR3 expression from pTa toward pT3 cases in a sample of BCa cases. FGFR3 was also positive in 45, 26, and 30% of G1, G2 and G3 cases, respectively. Moreover, there was association between mutation and FGFR3 over expression which were frequent in primary stage (pTa and pT1) and low grade (G1 and G2) BCa tumors [87]. It has been shown that there was FGFR3 up regulation in a sample of BCa tumor tissues compared with normal mucosa. Tumor size was also correlated with FGFR3 expression. Moreover, the up regulations of FGFR3, PI3Kp110, PI3KClassIII, and AKT were also correlated with recurrence free survival among T1 BCa patients [88]. ERCC1 over expression and FGFR3 mutation were associated with a better response to the non-adjuvant chemotherapy in a group of MIBC patients [89]. It has been shown that the mRNA levels of FGFR1 and CK20 were significantly higher in BCa tissues in comparison with normal margins. The invasive tumors had significantly higher levels of FGFR1 and CK20 expressions compared with non-invasive tumors. FGFR1 or CK20 were sensitive markers to separate the invasive and non-invasive tumors. The levels of FGFR1 and CK20 expressions were significantly higher in invasive tumors (pT2-pT4) compared with non-invasive tumors (pTis, pTa, and pT1). The expression levels of FGFR1 and CK20 were also correlated with stage and grade [90].

RTK classes of VIII, IX, and XIII

Tumor is limited to the mucosal layer in almost 70% of the new BCa cases. The rest of patients have an advanced tumor stages with local lymph node involvement, muscles invasion, and distant metastases at the time of diagnosis. About 50% of the MIBC patients does not respond to chemotherapy, radiotherapy, or surgical resection which results in a survival time lower than 5 years [116, 150]. The gold standard treatment option for BCa patients with distant metastases is the Platinum-based chemotherapy which has a 15% of 5-year survival rate and a median survival of 15 months [151]. MET is a cell surface RTK mainly produced in epithelial cells. MET signaling is critical for normal cellular development and homeostasis; however, it has also been shown to be involved in invasive tumors and distant metastasis [152]. It has been reported that the urinary MET levels could be an efficient marker of differentiating between BCa patients and healthy subjects, and also differentiating between MIBC and NMIBC patients [91]. Although, pharmaceutical inhibition of the RTK pathway function using Gefitinib had modest outcomes, it remains the gold standard treatment for BCa patients [153, 154]. The activation of c-MET by hepatocyte growth factor (HGF) worsen the malignant features of tumor cells which results in a higher rate of cells motility, proliferation, metastasis, and invasion [155]. Activation of c-MET induces other signaling proteins such as GRB2, GAB1, SHC, PLC1, and PI3-K [156]. Microarray analysis on RTK indicated that the PDGFR and AXL have interaction with c-MET [157]. It has been reported that the lack of c-MET expression renders less aggressiveness and more Cisplatin response in BCa. In contrast, c-MET up regulation had a significant association with worse clinical outcome and shorter overall survival among MIBC patients. The PDGFRL up regulation was also significantly correlated with a poorer prognosis. Moreover, NMIBC patients had an increased levels of AXL and PDGFR expressions compared with MIBC patients [92]. Recepteur d’Origine Nantais (RON) is a particular receptor tyrosine-kinase in the MET family [158]. It has been shown that there were correlations between RON or MET expressions and tumor aggressiveness and reduced survival. RON up regulation promoted the cell proliferation and migration. RON expression was also directly correlated with grade, size, and tumor stage among BCa patients. Moreover, RON/MET expression was correlated with reduced overall survival [93]. The Eph receptor is belonged to the RTK family that is regulated by ephrin ligands. Eph-ephrin interaction is associated with cell migration and neoplastic transformation [159]. It has been reported that there was a significant EphA2 up regulation in a sample of urothelial tumors compared with normal tissues. The levels of EphA2 expression was also significantly correlated with tumor stage. Moreover, there was a converse correlation between E-cadherin and EphA2 expressions in advanced tumor stages [94]. EphB4 is a member of the Eph receptors which has key functions in angiogenesis, neural development, and pattern formation [160,161,162,163]. EphB4 and its specific ligand, EphrinB2, are both transmembrane proteins that are typically expressed on venous and arterial endothelium, respectively. Deregulation of EphB4 has been demonstrated in various tumors of breast, prostate, and lung [164,165,166,167]. Activation of EphB4 regulates cell attachment and migration [168,169,170,171]. Frequent EphB4 up regulation was reported among a sample of BCa patients. While, majority of tumor tissues showed a high expression of EphB4, normal urothelial cells displayed very little or lack of EphB4 expression. P53 is a regulator of EphB4 via MAPK and PI3K signaling pathways. EphB4 was up regulated by PI3K/AKT pathway. The EphB4 suppression also reduced tumor cells invasion which can be due to MMP9 down regulation. Moreover, they observed BCL-XL down regulation following the EphB4 knockdown in BCa cells. Therefore, EphB4 suppression reduced tumor progression and increased apoptosis [95]. Discoidin domain receptors (DDRs) are a class of RTKs which are activated by collagens. DDR1 can be activated by most collagen types, whereas DDR2 can be activated only by type I and III collagens [172]. The collagen-DDR1 binding increases the self-renewal and migration of non-cancerous cells [173, 174]. A high level of DDR1 in solid malignant tumors was associated with poor prognosis [175]. It has been reported that there was a significant increased levels of DDR1 expression in BCa tissues which was associated with poor prognosis. DDR1 activation also increased tumor invasion through ZEB1 and SLUG up regulations in bladder tumor cells [96]. DDR2 promotes the EMT through the ECM blockade. The activated DDR2 becomes docking sites for adaptor proteins, resulting in the MMP2 up-regulation [176]. It has been observed that there was a significant DDR2 up regulation in a sample of urothelial carcinoma patients which was associated with poor prognosis, infiltrative pattern, higher grade, advanced T stage, and metastatic status [97].

Other tyrosine-kinase receptors

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors associated with neural differentiation and survival through binding to the Tropomyosin receptor kinase B (TrKB) [177]. BDNF/TrKB pathway has been reported to be involved in different solid cancers such as lung, prostate, and pancreatic ducts [178,179,180]. It has been observed that there were increased levels of BDNF and TrKB expressions among a sub population of transitional cell carcinomas (TCC) patients compared with healthy subjects. However, differences were significant in grade 3 TCC for BDNF expression, and in grade 1 and 3 TCC for TrKB expression. Therefore, TrKB and/or BDNF up regulation can be introduced as efficient markers of early detection among BCa patients [98]. C-KIT is a tyrosine-kinase receptor involving in carcinogenesis and hematopoiesis [181, 182]. The c-KIT up regulation has been reported in various cancers such as gastrointestinal, lung, and breast cancers [183,184,185]. Since, c-KIT up regulation has been observed in a marked population of a sample of small cell BCa patients, c-KIT targeted therapies can be an effective therapeutic method among these patients [99]. The c-KIT has key developmental functions and mainly expressed in melanocytes, interstitial cells of Cajal, erythroid and mast cell lineages [186,187,188]. The prevalence of c-KIT mutation and its expression levels were assessed in a sub population of bladder SCC patients which showed c-KIT up regulation in majority of cases. Bilharzial ova positive patients also showed a significantly higher expression levels of c-KIT compared with Bilharzial ova negative cases [100].

Non-receptor tyrosine-kinases

Feline Sarcoma (FES) and FES-related protein (FER) are a separate sub-family of non-receptor tyrosine-kinases [189]. Down regulation of FES represses the progression of renal cell carcinoma cells [190]. It was also shown that the increased FES expression was associated with a more aggressive tumor and shorter recurrence-free survival following surgical resection [191]. The FES was significantly down regulated in tumor cells compared with normal urothelial cells. A positive association was also observed between FES expression level and tumor cells invasion in patients with high-grade tumors. Moreover, FES up regulation was determined as a negative prognostic predictor of metastasis after radical surgery in patients with high-grade malignancies [101]. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute a subfamily of protein kinases which have the ability to phosphorylate aromatic (tyrosine) besides aliphatic (serine and threonine) residues [192,193,194]. DYRKs are involved in regulation of cellular proliferation, differentiation, and survival [195, 196]. DYRK2 stimulates cell apoptosis following DNA damages by p53 phosphorylation during genotoxic stress [197]. It has been reported that there was a significant correlation between DYRK2 over expression and higher disease-specific survival among chemotherapeutic-treated T1 high-grade and T2 BCa patients. Therefore, assessing the levels of DYRK2 could be a predictive factor to detect patients with T1 high-grade and T2 BCa that will probably show a good response to neoadjuvant chemotherapeutic treatment [102]. Epithelial and endothelial tyrosine-kinase (ETK) is a family of non-receptor tyrosine-kinases which can be activated by cytokines, hormones, growth factors, and ECM [198]. ETK is involved in regulation of cell proliferation, differentiation, motility, and survival. It has been reported that the ETK levels rises gradually during the BCa progression. There were also significant correlations between ETK up regulation, higher tumor grade, and poor prognosis. Suppression of ETK in bladder tumors reduced activity of AKT and STAT3. Therefore, the ETK over expression can be the reason of increased AKT and STAT3 activity in bladder tumors [103].

Conclusions

It was observed that the class I and V of RTKs were the most reported tyrosine-kinases among BCa patients in the world. This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BCa:

Bladder cancer

US:

United States

NMIBC:

Non-muscle-invasive bladder cancer

MIBC:

Muscle-invasive bladder cancer

TKs:

Tyrosine-kinases

EGFR:

Epidermal growth factor receptor

PDGFR:

Platelet-derived growth factor receptor

VEGFR:

Vascular endothelial growth factor receptor

FGFR:

Fibroblast growth factor receptor

HGFR:

Hepatocyte growth factor receptor

TKIs:

Tyrosine-kinase inhibitors

RTKs:

Receptors of tyrosine-kinases

FASN:

Fat synthase

UUTUC:

Upper urinary tract urothelial carcinoma

HRG:

Heregulin

MPUC:

Micropapillary urothelial carcinoma

IGF1R:

Insulin-like growth factor-1 receptor

bFGF:

Basic Fibroblast Growth Factor

CIS:

Carcinoma in situ

HGF:

Hepatocyte growth factor

RON:

Recepteur d’Origine Nantais

BDNF:

Brain-derived neurotrophic factor

TCC:

Transitional cell carcinomas

FES:

Feline Sarcoma

FER:

FES-related protein

ETK:

Epithelial and endothelial tyrosine-kinase

PI3K:

Phosphatidylinositol 3-kinase

DDRs:

Discoidin domain receptors

References

  1. 1.

    Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Google Scholar 

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  3. 3.

    Antoni S, et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.

    PubMed  Google Scholar 

  4. 4.

    Taylor JA, Kuchel GA. Bladder cancer in the elderly: clinical outcomes, basic mechanisms, and future research direction. Nat Clin Pract Urol. 2009;6(3):135–44.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lombard AP, Mudryj M. The emerging role of the androgen receptor in bladder cancer. Endocr Relat Cancer. 2015;22(5):R265–77.

    CAS  PubMed  Google Scholar 

  6. 6.

    Volanis D, et al. Environmental factors and genetic susceptibility promote urinary bladder cancer. Toxicol Lett. 2010;193(2):131–7.

    CAS  PubMed  Google Scholar 

  7. 7.

    Mojarrad M, Moghbeli M. Genetic and molecular biology of bladder cancer among Iranian patients. Mol Genet Genomic Med. 2020;1:e1233.

    Google Scholar 

  8. 8.

    Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet. 2009;374(9685):239–49.

    CAS  PubMed  Google Scholar 

  9. 9.

    Sanli O, et al. Bladder cancer. Lancet. 2017;3(1):1–19.

    Google Scholar 

  10. 10.

    Martinez Rodriguez RH, Buisan Rueda O, Ibarz L. Bladder cancer: present and future. Med Clin (Barc). 2017;149(10):449–55.

    Google Scholar 

  11. 11.

    Vasekar M, Degraff D, Joshi M. Immunotherapy in bladder cancer. Curr Mol Pharmacol. 2016;9(3):242–51.

    CAS  PubMed  Google Scholar 

  12. 12.

    Martin-Doyle W, Kwiatkowski DJ. Molecular biology of bladder cancer. Hematol Oncol Clin North Am. 2015;29(2):191–203.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Manning G, et al. The protein kinase complement of the human genome. Science. 2002;298(5600):1912–34.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hubbard MJ, Cohen P. On target with a new mechanism for the regulation of protein phosphorylation. Trends Biochem Sci. 1993;18(5):172–7.

    CAS  PubMed  Google Scholar 

  15. 15.

    Nattel S, et al. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87(2):425–56.

    CAS  PubMed  Google Scholar 

  16. 16.

    Hanks SK, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995;9(8):576–96.

    CAS  PubMed  Google Scholar 

  17. 17.

    Robinson DR, Wu Y-M, Lin S-F. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–57.

    CAS  PubMed  Google Scholar 

  18. 18.

    Pusztai L, et al. Growth factors: regulation of normal and neoplastic growth. J Pathol. 1993;169(2):191–201.

    CAS  PubMed  Google Scholar 

  19. 19.

    Moghbeli M, et al. Association of PYGO2 and EGFR in esophageal squamous cell carcinoma. Med Oncol. 2013;30(2):516.

    PubMed  Google Scholar 

  20. 20.

    Moghbeli M, et al. ErbB1 and ErbB3 co-over expression as a prognostic factor in gastric cancer. Biol Res. 2019;52(1):2.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.

    CAS  PubMed  Google Scholar 

  22. 22.

    Lahiry P, et al. Kinase mutations in human disease: interpreting genotype–phenotype relationships. Nat Rev Genet. 2010;11(1):60–74.

    CAS  PubMed  Google Scholar 

  23. 23.

    Karpov OA, et al. Receptor tyrosine kinase structure and function in health and disease; 2015.

    Google Scholar 

  24. 24.

    Mitra AP, Cote RJ. Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol. 2009;4:251–85.

    CAS  PubMed  Google Scholar 

  25. 25.

    McDonell LM, et al. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum Mol Genet. 2015;24(R1):R60–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Hänze J, et al. Effects of multi and selective targeted tyrosine kinase inhibitors on function and signaling of different bladder cancer cells. Biomed Pharmacother. 2018;106:316–25.

    PubMed  Google Scholar 

  27. 27.

    Kim SH, et al. Bgj398, a pan-fgfr inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with fgfr1 overexpression. Int J Mol Sci. 2018;19(10):3164.

    PubMed Central  Google Scholar 

  28. 28.

    Agarwal PK, et al. Emerging drugs for targeted therapy of bladder cancer. Expert Opin Emerg Drugs. 2007;12(3):435–48.

    CAS  PubMed  Google Scholar 

  29. 29.

    Alonso-Gordoa T, et al. Targeting tyrosine kinases in renal cell carcinoma:“new bullets against old guys”. Int J Mol Sci. 2019;20(8):1901.

    CAS  PubMed Central  Google Scholar 

  30. 30.

    Li Q, et al. MicroRNAs: key players in bladder cancer. Mol Diagn Ther. 2019;23(5):579–601.

    PubMed  Google Scholar 

  31. 31.

    Soria F, et al. Molecular markers in bladder cancer. World J Urol. 2019;37(1):31–40.

    PubMed  Google Scholar 

  32. 32.

    Coombs L, et al. Immunocytochemical localization of c-erbB-2 protein in transitional cell carcinoma of the urinary bladder. J Pathol. 1993;169(1):35–42.

    CAS  PubMed  Google Scholar 

  33. 33.

    Simon R, et al. HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer. 2003;107(5):764–72.

    CAS  PubMed  Google Scholar 

  34. 34.

    Nadoushan MRJ, et al. Overexpression of HER-2/neu oncogene and transitional cell carcinoma of bladder. Urol J. 2009;4(3):151–4.

    Google Scholar 

  35. 35.

    Krüger S, et al. HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications. Int J Cancer. 2002;102(5):514–8.

    PubMed  Google Scholar 

  36. 36.

    Coogan CL, et al. HER-2/neu protein overexpression and gene amplification in human transitional cell carcinoma of the bladder. Urology. 2004;63(4):786–90.

    PubMed  Google Scholar 

  37. 37.

    Latif Z, et al. HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy? Eur J Cancer. 2004;40(1):56–63.

    CAS  PubMed  Google Scholar 

  38. 38.

    Latif Z, et al. HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer. 2003;89(7):1305–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Fleischmann A, et al. Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol. 2011;60(2):350–7.

    CAS  PubMed  Google Scholar 

  40. 40.

    Hansel DE, et al. HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. Am J Clin Pathol. 2008;130(2):74–281.

    Google Scholar 

  41. 41.

    Eissa S, et al. HER2/neu expression in bladder cancer: relationship to cell cycle kinetics. Clin Biochem. 2005;38(2):142–8.

    CAS  PubMed  Google Scholar 

  42. 42.

    Abdelrahman AE, et al. Fatty acid synthase, Her2/neu, and E2F1 as prognostic markers of progression in non-muscle invasive bladder cancer. Ann Diagn Pathol. 2019;39:42–52.

    PubMed  Google Scholar 

  43. 43.

    Ding W, et al. Human epidermal growth factor receptor 2: a significant indicator for predicting progression in non-muscle-invasive bladder cancer especially in high-risk groups. World J Urol. 2015;33(12):1951–7.

    CAS  PubMed  Google Scholar 

  44. 44.

    Breyer J, et al. ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC). Virchows Arch. 2016;469(5):547–52.

    CAS  PubMed  Google Scholar 

  45. 45.

    Arikan O, et al. Clinical significance of serum and urinary HER2/neu protein levels in primary non-muscle invasive bladder cancer. Int Braz J Urol. 2015;41(6):1080–7.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kolla SB, et al. Prognostic significance of Her2/neu overexpression in patients with muscle invasive urinary bladder cancer treated with radical cystectomy. Int Urol Nephrol. 2008;40(2):321–7.

    PubMed  Google Scholar 

  47. 47.

    Koga F, et al. ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer. PLoS One. 2011;6(11):e27616.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Inoue M, et al. Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach. Int J Radiat Oncol Biol Phys. 2014;90(2):303–11.

    CAS  PubMed  Google Scholar 

  49. 49.

    Sasaki Y, et al. HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients. Int J Clin Exp Pathol. 2014;7(2):699.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Kim B, et al. HER2 protein overexpression and gene amplification in plasmacytoid urothelial carcinoma of the urinary bladder. Dis Markers. 2016;2016:1.

    Google Scholar 

  51. 51.

    Memon AA, et al. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer. 2004;91(12):2034–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Gunes S, et al. ErbB receptor tyrosine kinase family expression levels in urothelial bladder carcinoma. Pathol Res Pract. 2013;209(2):99–104.

    CAS  PubMed  Google Scholar 

  53. 53.

    Turkeri LN, et al. Impact of the expression of epidermal growth factor, transforming growth factor alpha, and epidermal growth factor receptor on the prognosis of superficial bladder cancer. Urology. 1998;51(4):645–9.

    CAS  PubMed  Google Scholar 

  54. 54.

    Popov Z, et al. Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. In: Urologic oncology: seminars and original investigations; 2004. Elsevier.

    Google Scholar 

  55. 55.

    Arfaoui AT, et al. Prognostic value of immunohistochemical expression profile of epidermal growth factor receptor in urothelial bladder cancer. J Immunoass Immunochem. 2016;37(4):359–67.

    CAS  Google Scholar 

  56. 56.

    Berger M, et al. Evaluation of epidermal growth factor receptors in bladder tumours. Br J Cancer. 1987;56(5):533–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Khaled HM, et al. Clinical significance of altered nm23-H1, EGFR, RB and p53 expression in bilharzial bladder cancer. BMC Cancer. 2009;9(1):32.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Lipponen P, Eskelinen M. Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erb B-2, p53) expression and long-term prognosis. Br J Cancer. 1994;69(6):1120–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Memon AA, et al. The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Br J Cancer. 2006;94(11):1703–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Kim W, et al. S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol. 2014;25(5):974–9.

    CAS  PubMed  Google Scholar 

  61. 61.

    Colquhoun A, et al. Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer. Clin Oncol. 2006;18(9):702–9.

    CAS  Google Scholar 

  62. 62.

    Thøgersen V, et al. Expression of transforming growth factor alpha and epidermal growth factor receptor in human bladder cancer. Scand J Clin Lab Invest. 1999;59(4):267–77.

    PubMed  Google Scholar 

  63. 63.

    Mansour AM, et al. Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer. BMC Urol. 2018;18(1):100.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Bryan RT, et al. Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM. Br J Cancer. 2015;112(6):1052–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Chu H, et al. EGFR 3’ UTR 774T> C polymorphism contributes to bladder cancer risk. Mutagenesis. 2013;28(1):49–55.

    CAS  PubMed  Google Scholar 

  66. 66.

    Mason RA, et al. EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis. Carcinogenesis. 2009;30(7):1155–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Li J, et al. Comparison of tyrosine kinase receptors HER2, EGFR, and VEGFR expression in micropapillary urothelial carcinoma with invasive urothelial carcinoma. Target Oncol. 2015;10(3):355–63.

    PubMed  Google Scholar 

  68. 68.

    Rajjayabun PH, et al. erbB receptor expression patterns in human bladder cancer. Urology. 2005;66(1):196–200.

    CAS  PubMed  Google Scholar 

  69. 69.

    Imai T, et al. Significance of epidermal growth factor receptor and c-erb B-2 protein expression in transitional cell cancer of the upper urinary tract for tumour recurrence at the urinary bladder. Br J Cancer. 1995;71(1):69–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Li W, et al. Overexpression of epidermal growth factor receptor (EGFR) and HER-2 in bladder carcinoma and its association with patients’ clinical features. Med Sci Monit. 2018;24:7178.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kassouf W, et al. Distinctive expression pattern of ErbB family receptors signifies an aggressive variant of bladder cancer. J Urol. 2008;179(1):353–8.

    PubMed  Google Scholar 

  72. 72.

    Gonzalez-Roibon N, et al. Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy. Urology. 2014;83(6):1444.e1–6.

    Google Scholar 

  73. 73.

    Rochester MA, et al. The type 1 insulin-like growth factor receptor is over-expressed in bladder cancer. BJU Int. 2007;100(6):1396–401.

    PubMed  Google Scholar 

  74. 74.

    Metalli D, et al. The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and mitogen-activated protein kinase-dependent activation of paxillin. Am J Pathol. 2010;176(6):2997–3006.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Iozzo RV, Schaefer L. Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J. 2010;277(19):3864–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Marzioni D, et al. Expression of basic fibroblast growth factor, its receptors and syndecans in bladder cancer. Int J Immunopathol Pharmacol. 2009;22(3):627–38.

    CAS  PubMed  Google Scholar 

  77. 77.

    Duenas M, et al. PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors. Mol Carcinog. 2015;54(7):566–76.

    CAS  PubMed  Google Scholar 

  78. 78.

    Juanpere N, et al. Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer. Hum Pathol. 2012;43(10):1573–82.

    CAS  PubMed  Google Scholar 

  79. 79.

    Kompier LC, et al. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One. 2010;5:11.

    Google Scholar 

  80. 80.

    Pandith AA, et al. Oncogenic activation of fibroblast growth factor receptor-3 and RAS genes as non-overlapping mutual exclusive events in urinary bladder cancer. Asian Pac J Cancer Prev. 2016;17(6):2787–93.

    PubMed  Google Scholar 

  81. 81.

    Bertz S, et al. Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer. Virchows Arch. 2014;465(6):687–95.

    CAS  PubMed  Google Scholar 

  82. 82.

    Billerey C, et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 2001;158(6):1955–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    van Oers JM, et al. FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumours. Eur Urol. 2007;52(3):760–8.

    PubMed  Google Scholar 

  84. 84.

    van Oers JM, et al. FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur Urol. 2009;55(3):650–7.

    PubMed  Google Scholar 

  85. 85.

    Mhawech-Fauceglia P, et al. FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Eur J Surg Oncol (EJSO). 2006;32(2):231–7.

    CAS  Google Scholar 

  86. 86.

    Breyer J, et al. High CDKN2A/p16 and low FGFR3 expression predict progressive potential of stage pT1 urothelial bladder carcinoma. Clin Genitourin Cancer. 2018;16(4):248–256. e2.

    PubMed  Google Scholar 

  87. 87.

    Bodoor K, et al. FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population. Cancer Epidemiol. 2010;34(6):724–32.

    CAS  PubMed  Google Scholar 

  88. 88.

    Pedregosa AB, et al. Expresión de las proteínas FGFR3, PI3K, AKT, p21Waf1/Cip1 y ciclinas D1 y D3 en pacientes con tumores de vejiga T1: implicaciones clínicas y significado pronóstico. Actas Urol Esp. 2017;41(3):172–80.

    Google Scholar 

  89. 89.

    Yang Z, et al. Somatic FGFR3 mutations distinguish a subgroup of muscle-invasive bladder cancers with response to neoadjuvant chemotherapy. EBioMedicine. 2018;35:198–203.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Abdul-Maksoud RS, et al. Fibroblast growth factor receptor 1 and cytokeratin 20 expressions and their relation to prognostic variables in bladder cancer. Gene. 2016;591(2):320–6.

    CAS  PubMed  Google Scholar 

  91. 91.

    McNeil BK, et al. Preliminary evaluation of urinary soluble met as a biomarker for urothelial carcinoma of the bladder. J Transl Med. 2014;12(1):199.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Kim Y-W, et al. The c-MET network as novel prognostic marker for predicting bladder cancer patients with an increased risk of developing aggressive disease. PLoS One. 2015;10(7):e0134552.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Cheng H-L, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005;92(10):1906–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Abraham S, et al. Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder. Clin Cancer Res. 2006;12(2):353–60.

    CAS  PubMed  Google Scholar 

  95. 95.

    Xia G, et al. EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival. Oncogene. 2006;25(5):769–80.

    CAS  PubMed  Google Scholar 

  96. 96.

    Xie X, et al. Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer. Am J Transl Res. 2017;9(5):2500–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Tsai MC, et al. DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study. Oncotarget. 2016;7(48):78918–31.

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Lai PC, Chiu TH, Huang YT. Overexpression of BDNF and TrkB in human bladder cancer specimens. Oncol Rep. 2010;24(5):1265–70.

    PubMed  Google Scholar 

  99. 99.

    Pan C-X, et al. C-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol. 2005;18(3):320–3.

    CAS  PubMed  Google Scholar 

  100. 100.

    Shams TM, Metawea M, Salim EI. C-KIT positive Schistosomal urinary bladder carcinomas are frequent but lack KIT gene mutations. Asian Pac J Cancer Prev. 2013;14(1):15–20.

    PubMed  Google Scholar 

  101. 101.

    Asai A, et al. Pathological significance and prognostic significance of FES expression in bladder cancer vary according to tumor grade. J Cancer Res Clin Oncol. 2018;144(1):21–31.

    CAS  PubMed  Google Scholar 

  102. 102.

    Nomura S, et al. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) as a novel marker in T1 high-grade and T2 bladder cancer patients receiving neoadjuvant chemotherapy. BMC Urol. 2015;15(1):53.

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Guo S, et al. Tyrosine kinase ETK/BMX is up-regulated in bladder cancer and predicts poor prognosis in patients with cystectomy. PLoS One. 2011;6(3):e17778.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Hynes NE, Lane HA. Myc and mammary cancer: Myc is a downstream effector of the ErbB2 receptor tyrosine kinase. J Mammary Gland Biol Neoplasia. 2001;6(1):141–50.

    CAS  PubMed  Google Scholar 

  105. 105.

    Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39–51.

    CAS  PubMed  Google Scholar 

  106. 106.

    Coombs LM, et al. Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. Br J Cancer. 1991;63(4):601–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Sato K, et al. An immunohistologic evaluation of C-erbB-2 gene product in patients with urinary bladder carcinoma. Cancer. 1992;70(10):2493–8.

    CAS  PubMed  Google Scholar 

  108. 108.

    Wolff AC, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2014;138(2):241–56.

    Google Scholar 

  109. 109.

    Reznikoff CA, et al. Genetic alterations and biological pathways in human bladder cancer pathogenesis. In: Urologic oncology: seminars and original investigations; 2000. Elsevier.

    Google Scholar 

  110. 110.

    Mellon JK, et al. C-erbB-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value. J Urol. 1996;155(1):321–6.

    CAS  PubMed  Google Scholar 

  111. 111.

    Miyamoto H, et al. C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. Urology. 2000;55(5):679–83.

    CAS  PubMed  Google Scholar 

  112. 112.

    Moriyama M, et al. Expression of c-erbB-2 gene product in urinary bladder cancer. J Urol. 1991;145(2):423–7.

    CAS  PubMed  Google Scholar 

  113. 113.

    Sauter G, et al. Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res. 1993;53(10):2199–203.

    CAS  PubMed  Google Scholar 

  114. 114.

    Underwood M, et al. C-erbB-2 gene amplification: a molecular marker in recurrent bladder tumors? Cancer Res. 1995;55(11):2422–30.

    CAS  PubMed  Google Scholar 

  115. 115.

    Fleischmann A, et al. Extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is an independent prognostic factor. J Clin Oncol. 2005;23(10):2358–65.

    PubMed  Google Scholar 

  116. 116.

    Stein JP, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666–75.

    CAS  PubMed  Google Scholar 

  117. 117.

    Garcia JA, Dreicer R. Systemic chemotherapy for advanced bladder cancer: update and controversies. J Clin Oncol. 2006;24(35):5545–51.

    CAS  PubMed  Google Scholar 

  118. 118.

    Marín ÁP, et al. Role of anti-her-2 therapy in bladder carcinoma. J Cancer Res Clin Oncol. 2010;136(12):1915–20.

    PubMed  Google Scholar 

  119. 119.

    Grube S, et al. Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with orlistat reduces cell viability and triggers apoptosis. J Neuro-Oncol. 2014;118(2):277–87.

    CAS  Google Scholar 

  120. 120.

    Jensen-Urstad AP, et al. Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα. J Lipid Res. 2013;54(7):1848–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Lopez-Beltran A, et al. Plasmacytoid urothelial carcinoma of the bladder. Hum Pathol. 2009;40(7):1023–8.

    PubMed  Google Scholar 

  122. 122.

    Ro JY, et al. Plasmacytoid transitional cell carcinoma of urinary bladder: a clinicopathologic study of 9 cases. Am J Surg Pathol. 2008;32(5):752–7.

    PubMed  Google Scholar 

  123. 123.

    Burden S, Yarden Y. Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis. Neuron. 1997;18(6):847–55.

    CAS  PubMed  Google Scholar 

  124. 124.

    Le X-F, et al. Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. Clin Cancer Res. 2000;6(1):260–70.

    CAS  PubMed  Google Scholar 

  125. 125.

    Le X-F, Varela C, Bast R. Heregulin-induced apoptosis. Apoptosis. 2002;7(6):483–91.

    CAS  PubMed  Google Scholar 

  126. 126.

    Olayioye MA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19(13):3159–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.

    CAS  PubMed  Google Scholar 

  128. 128.

    Tzahar E, et al. Bivalence of EGF-like ligands drives the ErbB signaling network. EMBO J. 1997;16(16):4938–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Pinkas-Kramarski R, et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 1996;15(10):2452–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Guy PM, et al. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci U S A. 1994;91(17):8132–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol. 2005;174(1):14–20.

    CAS  PubMed  Google Scholar 

  132. 132.

    Sternberg C. The treatment of advanced bladder cancer. Ann Oncol. 1995;6(2):113–26.

    CAS  PubMed  Google Scholar 

  133. 133.

    Saxman SB, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997;15(7):2564–9.

    CAS  PubMed  Google Scholar 

  134. 134.

    von der Maase H, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–8.

    PubMed  Google Scholar 

  135. 135.

    Amin MB, et al. Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol. 1994;18(12):1224–32.

    CAS  PubMed  Google Scholar 

  136. 136.

    Lipponen PK. Expression of c-myc protein is related to cell proliferation and expression of growth factor receptors in transitional cell bladder cancer. J Pathol. 1995;175(2):203–10.

    CAS  PubMed  Google Scholar 

  137. 137.

    Le Roith D. Regulation of proliferation and apoptosis by the insulin-like growth factor I receptor. Growth Hormon IGF Res. 2000;10:S12–3.

    Google Scholar 

  138. 138.

    Theocharis AD, et al. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277(19):3904–23.

    CAS  PubMed  Google Scholar 

  139. 139.

    Iozzo RV, et al. Decorin antagonizes IGF receptor I (IGF-IR) function by interfering with IGF-IR activity and attenuating downstream signaling. J Biol Chem. 2011;286(40):34712–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Knowles MA, et al. Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer. Cancer Metastasis Rev. 2009;28(3–4):305–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Platt FM, et al. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009;15(19):6008–17.

    CAS  PubMed  Google Scholar 

  142. 142.

    Cantley LCJS. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–7.

    CAS  PubMed  Google Scholar 

  143. 143.

    van Rhijn BW, et al. Frequent FGFR3 mutations in urothelial papilloma. J Pathol. 2002;198(2):245–51.

    PubMed  Google Scholar 

  144. 144.

    van Rhijn BW, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol. 2003;21(10):1912–21.

    PubMed  Google Scholar 

  145. 145.

    Hernández S, et al. FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis. Clin Cancer Res. 2005;11(15):5444–50.

    PubMed  Google Scholar 

  146. 146.

    Zieger K, et al. Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res. 2005;11(21):7709–19.

    CAS  PubMed  Google Scholar 

  147. 147.

    Horton WA, Garofalo S, Lunstrum GP. FGFR3 signaling in achondroplasia: a review. Cell Mater. 1998;8:83–7.

    Google Scholar 

  148. 148.

    L'Hôte CG, Knowles MA. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res. 2005;304(2):417–31.

    PubMed  Google Scholar 

  149. 149.

    Powers C, McLeskey S, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer. 2000;7(3):165–97.

    CAS  PubMed  Google Scholar 

  150. 150.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

    PubMed  Google Scholar 

  151. 151.

    Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Ann Oncol. 2006;17(suppl_5):v118–22.

    PubMed  Google Scholar 

  152. 152.

    Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/met signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(6):553–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Ciardiello F. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74.

    CAS  PubMed  Google Scholar 

  154. 154.

    Noon AP, Catto JWF. Challenging current paradigms. Nat Rev Urol. 2013;10(2):67–8.

    CAS  PubMed  Google Scholar 

  155. 155.

    Peters S, Adjei AA. MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol. 2012;9(6):314.

    CAS  PubMed  Google Scholar 

  156. 156.

    Miyata Y, et al. Phosphorylated hepatocyte growth factor receptor/c-met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase–2 and–7 and E-cadherin. Hum Pathol. 2009;40(4):496–504.

    CAS  PubMed  Google Scholar 

  157. 157.

    Yeh C-Y, et al. Transcriptional activation of the Axl and PDGFR-α by c-met through a ras-and Src-independent mechanism in human bladder cancer. BMC Cancer. 2011;11(1):139.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Ronsin C, et al. A novel putative receptor protein tyrosine kinase of the met family. Oncogene. 1993;8(5):1195–202.

    CAS  PubMed  Google Scholar 

  159. 159.

    Dodelet VC, Pasquale EB. Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene. 2000;19(49):5614–9.

    CAS  PubMed  Google Scholar 

  160. 160.

    Pasquale EB. The Eph family of receptors. Curr Opin Cell Biol. 1997;9(5):608–15.

    CAS  PubMed  Google Scholar 

  161. 161.

    Gerety SS, et al. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell. 1999;4(3):403–14.

    CAS  PubMed  Google Scholar 

  162. 162.

    Holder N, Klein R. Eph receptors and ephrins: effectors of morphogenesis. Development. 1999;126(10):2033–44.

    CAS  PubMed  Google Scholar 

  163. 163.

    Tickle C, Altabef M. Epithelial cell movements and interactions in limb, neural crest and vasculature. Development. 1999;9(4):455–60.

    CAS  Google Scholar 

  164. 164.

    Andres AC, et al. Protein tyrosine kinase expression during the estrous cycle and carcinogenesis of the mammary gland. Int J Cancer. 1995;63(2):288–96.

    CAS  PubMed  Google Scholar 

  165. 165.

    Berclaz G, et al. Expression of the receptor protein tyrosine Kinasemyk-1/htkin Normal and malignant mammary epithelium. Biochem Biophys Res Commun. 1996;226(3):869–75.

    CAS  PubMed  Google Scholar 

  166. 166.

    Stephenson S-A, et al. Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol. 2001;2(1):15.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Takai N, et al. Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep. 2001;8(3):567–73.

    CAS  PubMed  Google Scholar 

  168. 168.

    Adams RH, et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 1999;13(3):295–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    O’Leary DD, Wilkinson DG. Eph receptors and ephrins in neural development. Curr Opin Neurobiol. 1999;9(1):65–73.

    PubMed  Google Scholar 

  170. 170.

    Oates AC, et al. An early developmental role for eph-ephrin interaction during vertebrate gastrulation. Mech Dev. 1999;83(1–2):77–94.

    CAS  PubMed  Google Scholar 

  171. 171.

    Steinle JJ, et al. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem. 2002;277(46):43830–5.

    CAS  PubMed  Google Scholar 

  172. 172.

    Vogel W. Discoidin domain receptors: structural relations and functional implications. FASEB J. 1999;13(Suppl):S77–82.

    CAS  PubMed  Google Scholar 

  173. 173.

    Suh HN, Han HJ. Collagen I regulates the self-renewal of mouse embryonic stem cells through alpha2beta1 integrin- and DDR1-dependent Bmi-1. J Cell Physiol. 2011;226(12):3422–32.

    CAS  PubMed  Google Scholar 

  174. 174.

    Yeh YC, Wang CZ, Tang MJ. Discoidin domain receptor 1 activation suppresses alpha2beta1 integrin-dependent cell spreading through inhibition of Cdc42 activity. J Cell Physiol. 2009;218(1):146–56.

    CAS  PubMed  Google Scholar 

  175. 175.

    Huo Y, et al. High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res. 2015;34:88.

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Ikeda K, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem. 2002;277(21):19206–12.

    CAS  PubMed  Google Scholar 

  177. 177.

    Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24(1):677–736.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Miknyoczki SJ, et al. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer. 1999;81(3):417–27.

    CAS  PubMed  Google Scholar 

  179. 179.

    Montano X, Djamgoz MBA. Epidermal growth factor, neurotrophins and the metastatic cascade in prostate cancer. FEBS Lett. 2004;571(1–3):1–8.

    CAS  PubMed  Google Scholar 

  180. 180.

    Ricci A, et al. Neurotrophins and neurotrophin receptors in human lung cancer. Am J Respir Cell Mol Biol. 2001;25(4):439–46.

    CAS  PubMed  Google Scholar 

  181. 181.

    Natali PG, et al. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992;52(22):6139–43.

    CAS  PubMed  Google Scholar 

  182. 182.

    Pietsch T, et al. Expression of the c-kit receptor and its ligand SCF in non-small-cell lung carcinomas. Int J Cancer. 1998;75(2):171–5.

    CAS  PubMed  Google Scholar 

  183. 183.

    Demetri GD. Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. In: Seminars in oncology; 2001. Elsevier.

    Google Scholar 

  184. 184.

    Potti A, et al. CD117 (c-KIT) overexpression in patients with extensive-stage small-cell lung carcinoma. Ann Oncol. 2003;14(6):894–7.

    CAS  PubMed  Google Scholar 

  185. 185.

    DiPaola RS, et al. Evidence for a functional kit receptor in melanoma, breast, and lung carcinoma cells. Cancer Gene Ther. 1997;4(3):176–82.

    CAS  PubMed  Google Scholar 

  186. 186.

    Yarden Y, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987;6(11):3341–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Zsebo KM, et al. Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990;63(1):213–24.

    CAS  PubMed  Google Scholar 

  188. 188.

    Tsuura Y, et al. Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Arch. 1994;424(2):135–41.

    CAS  PubMed  Google Scholar 

  189. 189.

    Greer PJNRMCB. Closing in on the biological functions of fps/Fes and Fer. Nat Rev Mol Cell Biol. 2002;3(4):278–89.

    CAS  PubMed  Google Scholar 

  190. 190.

    Kanda S, et al. Downregulation of the c-Fes protein-tyrosine kinase inhibits the proliferation of human renal carcinoma cells. Int J Oncol. 2009;34(1):89–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Miyata Y, et al. Pathological significance and predictive value for biochemical recurrence of c-Fes expression in prostate cancer. Prostate. 2012;72(2):201–8.

    CAS  PubMed  Google Scholar 

  192. 192.

    Campbell LE, Proud CG. Differing substrate specificities of members of the DYRK family of arginine-directed protein kinases. FEBS Lett. 2002;510(1–2):31–6.

    CAS  PubMed  Google Scholar 

  193. 193.

    HIMPEL S, et al. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001;359(3):497–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Becker W, Joost H-G. Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity, in Progress in nucleic acid research and molecular biology. Prog Nucleic Acid Res Mol Biol. 1998;62:1–17.

    Google Scholar 

  195. 195.

    Aranda S, Laguna A, de la Luna S. DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles. FASEB J. 2011;25(2):449–62.

    CAS  PubMed  Google Scholar 

  196. 196.

    Park J, et al. Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell Mol Life Sci. 2009;66(20):3235–40.

    CAS  PubMed  Google Scholar 

  197. 197.

    Taira N, et al. DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell. 2007;25(5):725–38.

    CAS  PubMed  Google Scholar 

  198. 198.

    Qiu Y, Kung HJ. Signaling network of the Btk family kinases. Oncogene. 2000;19(49):5651–61.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

Not applicable.

Author information

Affiliations

Authors

Contributions

ASZ, AHB, HRR, and MMojarrad were involved in search strategy and drafting. MMoghbeli supervised the project and revised and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Meysam Moghbeli.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zangouei, A.S., Barjasteh, A.H., Rahimi, H.R. et al. Role of tyrosine kinases in bladder cancer progression: an overview. Cell Commun Signal 18, 127 (2020). https://doi.org/10.1186/s12964-020-00625-7

Download citation

Keywords

  • Bladder cancer
  • Tyrosine-kinase
  • Diagnosis
  • Targeted therapy
  • Panel marker