Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer

An, Bo; Kilgour, Elaine; Smith, Paul D.

doi:10.1158/1078-0432.ccr-11-0699

Cited by 382 publications

(375 citation statements)

References 52 publications

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“…30 Therefore, it is thought that FGFR2 signaling has a crucial role in the maintenance of cancer stemness properties such as sphere formation and in vivo tumor initiation in ovarian cancer HTBoA cells. FGF4 production is induced in CSCs/CICs by stimulation of fibroblast-secreting factors and then FGF4 promotes tumor initiation through autocrine and paracrine mechanisms ( Figure 9).…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Yasuda

Torigoe

Mariya

et al. 2014

Laboratory Investigation

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Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/ CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1 high ) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1 high cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1 high cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1 high cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1 high cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1 high cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1 high cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.

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Section: Discussionmentioning

confidence: 99%

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Yasuda

Torigoe

Mariya

et al. 2014

Laboratory Investigation

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“…These diverse ligand-receptor combinations mediate multiple developmental programs during embryogenesis, as well as adult tissue repair and maintenance. Elevated FGFR1 expression and upregulation of FGFR/ FGF signaling apparently lead to cell transformation and lung carcinogenesis (20)(21)(22)(23)(24), and negatively affects the survival of patients (14,25). It has been demonstrated, using cell cultures and xenografted mouse models, that SCC carrying FGFR1 gene amplifications responds effectively to therapy that blocks FGFR1 activity (14,26), revealing the first high-frequency targetable oncogene specific for smoking-associated lung cancer (27).…”

Section: Introductionmentioning

confidence: 99%

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Sokołowska-Wędzina

Chodaczek

Chudzian

et al. 2017

Molecular Cancer Research

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Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smokingassociated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. Ó2017 AACR.

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“…A following phase 3 rilotumumab trial (RILOMET-1) in patients with advanced MET-positive gastric or gastroesophageal junction adenocarcinoma is ongoing [10]. Some new agents inhibiting FGFR2 signaling have been developed for solid tumors, including gastric cancer [11]. Several reports have examined the relation between clinical factors, pathological features, and prognosis and the protein overexpression or gene amplification of these RTKs.…”

Section: Introductionmentioning

confidence: 99%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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Background Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). Methods We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization.Results The frequency of overexpression was 11.8 % for HER2, 23.5 % for EGFR, 24.9 % for MET and 31.1 % for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7 % of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9 % of the GACs, respectively. Conclusions Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.

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Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer

Cited by 382 publications

References 52 publications

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

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