Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain

Jin, Ling; Nonaka, Y.; Miyakawa, Shin; Fujiwara, Masatoshi; Nakamura, Yoshikazu

doi:10.1038/mt.2016.158

Cited by 40 publications

(38 citation statements)

References 69 publications

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“…Therefore, the role of Fgf2 in CAF pro‐tumourigenic activity was investigated using an anti‐ Fgf2 aptamer. Aptamers are short single‐stranded DNA or RNA molecules that are selected from random sequence libraries based on their highly specific and sensitive affinity to a target molecule . We co‐cultured CAFs with tumour cell‐enriched or WT lung epithelium in the 3D colony‐forming assay.…”

Section: Resultsmentioning

confidence: 99%

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Hegab

Ozaki

Kameyama

et al. 2019

The Journal of Pathology

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Cancer‐associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)‐dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma‐like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF‐secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell‐recruiting cytokines. CAFs also enhanced the conversion of tumour‐associated macrophages (TAMs) to the tumour‐supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr‐independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9‐induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Hegab

Ozaki

Kameyama

et al. 2019

The Journal of Pathology

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“…Tibiae were harvested and fixed by immersing in 10% NBF (Jin et al, 2016; Liu et al, 2016) for at least 2 days. These tibiae were then immersed in 15% w/v solution of UltraPure TM EDTA in phosphate buffer for at least 4 weeks, with the EDTA solution being changed twice per week (Hald et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

et al. 2017

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In the majority of patients with advanced breast cancer, there is metastatic spread to bones resulting in pain. Clinically available drug treatments for alleviation of breast cancer-induced bone pain (BCIBP) often produce inadequate pain relief due to dose-limiting side-effects. A major impediment to the discovery of novel well-tolerated analgesic agents for the relief of pain due to bony metastases is the fact that most cancer-induced bone pain models in rodents relied on the systemic injection of cancer cells, causing widespread formation of cancer metastases and poor general animal health. Herein, we have established an optimized, clinically relevant Wistar Han female rat model of breast cancer induced bone pain which was characterized using behavioral assessments, radiology, histology, immunohistochemistry and pharmacological methods. In this model that is based on unilateral intra-tibial injection (ITI) of Walker 256 carcinoma cells, animals maintained good health for at least 66 days post-ITI. The temporal development of hindpaw hypersensitivity depended on the initial number of Walker 256 cells inoculated in the tibiae. Hindpaw hypersensitivity resolved after approximately 25 days, in the continued presence of bone tumors as evidenced by ex vivo histology, micro-computed tomography scans and immunohistochemical assessments of tibiae. A possible role for the endogenous opioid system as an internal factor mediating the self-resolving nature of BCIBP was identified based upon the observation that naloxone, a non-selective opioid antagonist, caused the re-emergence of hindpaw hypersensitivity. Bolus dose injections of morphine, gabapentin, amitriptyline and meloxicam all alleviated hindpaw hypersensitivity in a dose-dependent manner. This is a first systematic pharmacological profiling of this model by testing standard analgesic drugs from four important diverse classes, which are used to treat cancer induced bone pain in the clinical setting. Our refined rat model more closely mimics the pathophysiology of this condition in humans and hence is well-suited for probing the mechanisms underpinning breast cancer induced bone pain. In addition, the model may be suitable for efficacy profiling of new molecules from drug discovery programs with potential to be developed as novel agents for alleviation of intractable pain associated with disseminated breast cancer induced bony metastases.

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“…14 Presently, only one aptamer drug (Macugen) has been approved by the FDA, but several others are being evaluated in clinical trials. 15 In addition, aptamers have been used to treat aging-related disorders, 16 obesity and diabetes mellitus, 17,18 cardiovascular diseases, 19 infectious diseases, 20,21 blood coagulation, 22 bone diseases, 23 immunological diseases, 24 and cancers 25 (Figure 2).…”

Section: Use Of Aptamers In Theranosticsmentioning

confidence: 99%

“…Fibroblast growth factor 2 (FGF2) plays a key role in bone remodeling and disease progression. Jin et al constructed a novel human FGF2-specific RNA aptamer, APT-F2, 23…”

Section: Use Of Aptamers In Theranosticsmentioning

confidence: 99%

<p>Aptamers as Versatile Ligands for Biomedical and Pharmaceutical Applications</p>

Guan¹,

Zhang²

2020

IJN

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Aptamers are a class of targeting ligands that bind exclusively to biomarkers of interest. Aptamers have been identified as candidates for the construction of various smart systems for therapy, diagnosis, bioimaging, and drug delivery due to their high target affinity and specificity. Aptamers are accounted as chemical antibodies that can be readily linked to drugs, sensors, signal enhancers, or nanocarriers for functionalization. Use of aptamer-guided medications, especially nanomedicines, has resulted in encouraging outcomes compared to those use of aptamer-free counterparts. This article reviews recent advances in the use of aptamers as targeting ligands for various biomedical and pharmaceutical purposes. Special interests focus on aptamer-based theranostics, biosensing, bioimaging, drug potentiation, and targeted drug delivery.

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Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain

Cited by 40 publications

References 69 publications

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

<p>Aptamers as Versatile Ligands for Biomedical and Pharmaceutical Applications</p>

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