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Title: Fibroblast growth factor receptors in chemoresistance
Author: Markert, Anja
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Chemoresistance is a major obstacle to successful treatment in many cancers. Identification and dissection of the mechanisms underlying chemoresistance is therefore crucial for finding new therapeutic targets to improve patient survival. One growth factor implicated in chemoresistance is FGF2. It has been shown to be involved in triggering chemoresistance in small cell lung cancer (SCLC) and osteosarcoma cells via the activation of a MAPK-dependent signalling pathway. Similarly, previous work by our group has shown that FGF10 induces chemoresistance in SCLC. Here, we investigated whether FGF2 and FGF10 play a role in chemoresistance in other cancer types, such as non-small cell lung cancer (NSCLC), breast cancer and osteosarcoma and which receptors are involved in mediating FGF2-induced chemoresistance. Furthermore we assessed the possible therapeutic benefits of a new FGF receptor inhibitor, either alone or in combination with chemotherapeutic drugs currently used in the clinic, such as cisplatin and etoposide. FGF2 initiated MAPK signalling in most of the cell lines tested, leading to increased proliferation in about 50% of them. However, it only induced chemoresistance to cisplatin and etoposide in the osteosarcoma cell line U2OS and protected the breast cancer cell line MCF7 from etoposide-induced cell death. Furthermore, FGF10 also triggered resistance to etoposide in MCF7 cells. In the absence of added growth factors, physiological concentrations of FGFR inhibitors did not affect cell survival or alter the cell's sensitivity to etoposide or cisplatin. However, it prevented FGF2-mediated activation of the MAPK signalling pathway and consequently abolished FGF2-mediated proliferation and chemoresistance. SiRNA-mediated knockdown of the individual FGF receptors showed that FGFR1 is the crucial receptor in mediating the chemoresistance effects of FGF2 in U2OS cells, as knockdown of this receptor abolished the activation of the MAPK pathway by FGF2 and reduced FGF2-induced chemoresistance. FGFR1 and FGFR2 were essential for U2OS cell survival. It has previously been shown, that FGFR1 is commonly overexpressed and/or overactivated in squamous cell carcinoma of the lungs; therefore, we tested the expression levels of FGFR1 in two independent sets of tissue microarrays (TMAs) of NSCLC biopsies. Overexpression of FGFR1 could only be found in 5 out of 151 and 3 out of 217 cases, respectively and this was more prevalent in adenocarcinoma than squamous cell carcinoma. To gain more insight into the mechanisms by which FGFR signalling leads to chemoresistance, we sought to analyse FGFR-target genes in an mRNA expression microarray. Inhibition or knockdown of FGFR1 and FGFR2 led to down-regulation of a variety of genes associated with apoptosis, inflammation, and proliferation, which could be involved in oncogenic processes or chemoresistance and thus be potential new targets for cancer treatment. However, the precise role of these genes in cancer biology and chemoresistance needs to be further investigated. Overall, our results indicate that FGF-mediated chemoresistance does not seem to be a widespread obstacle in NSCLC or breast cancer treatment. Nevertheless, FGFR signalling is crucially involved in survival signalling of U2OS cells and may thus provide an important target for treatment in a subgroup of cancers.
Supervisor: Pardo, Olivier ; Seckl, Michael Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available