Change in fibroblast growth factor 2 expression as an early phase radiotherapy‐responsive marker in sequential biopsy samples from patients with cervical cancer during fractionated radiotherapy

Abstract

BACKGROUND:The authors previously demonstrated that fibroblast growth factor 2 (FGF2) expression levels in tumor cells (FGF2-T) may be an indicator of the efficacy of radiotherapy in patients with cervical cancer (CC). In the current study, this finding was extended in newly enrolled patients and was investigated further in stromal FGF2 (FGF2-S) expression. METHODS: Sixty-nine patients with CC were recruited as a validation set for the immunohistochemical detection of FGF2-T from biopsy samples that were taken before (pretreatment) or 1 week after the initiation of radiotherapy (midtreatment). The authors also investigated the expression of FGF2 in tumor FGF2-S and investigated vascular endothelial growth factor (VEGF), and cluster of differentiation 31 (CD31) (also called platelet endothelial cell adhesion molecule) in these patients and in an additional 35 patients from a previous study. RESULTS: FGF2 expression was detected in tumor cells from all patients and in stromal cells from 87% of patients. FGF2-T was significantly higher in midtreatment samples (P = .0002), and a high ratio of midtreatment/pretreatment FGF2-T was related significantly to a better prognosis (P = .025). Increased VEGF expression after the initiation of radiotherapy was related significantly to positive FGF2-S in pretreatment samples (P = .035); however, it was not related to prognosis or microvessel density detected by CD31 expression. CONCLUSIONS: Radiation causes a response in tumor cells and adjacent normal cells and changes the extracellular matrix environment. In this study, the authors confirmed their previous findings and demonstrated that changes in FGF2-T expression may be used as a marker to monitor the effectiveness of radiotherapy in patients with CC. These findings should improve patient selection for molecular targeted therapies, such as cytokine inhibitors, after standard-of-care treatment. Cancer 2010;116:5082-92.

FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy

“…In our hands at higher doses a similar macrophage phenotype also was influenced by the absence or blocking of FGF2. We observed an increase in FGF2 following irradiation of tumours in mice similar to those described in several clinical reports [28][29][30]43,44 . Blocking FGF2 with a specific antibody led to diminished tumour regrowth after irradiation that was associated with an increase in M1 polarisation of TAMs.…”

“…6e). Thus, as reported in human rectal and cervical cancers [28][29][30][31] , radiotherapy led to increased total tumour content of FGF2 LMW , and FGF2 was found in TAMs.…”

“…In WT mice, TAMs were the major source of FGF2, and were the only immune cell to abundantly express FGFR1 and 2. FGF2 has been reported to be induced in irradiated human tumours [28][29][30][31] raising the possibility that FGF2 might be a useful therapeutic target for patients who have received radiotherapy. Accordingly, we examined the effect of FGF2 on the irradiation response, and found that a blocking antibody to FGF2 in combination with radiotherapy reduced or even eliminated tumour regrowth in association with an increase in the TAM iNOS + /CD206 + ratio (also called a M1/M2 ratio).…”

Upregulated expression of FGF13/FHF2 mediates resistance to platinum drugs in cervical cancer cells

“…These patients gave appropriate informed consent to allow examination of their tissues and medical records, and the study protocols were approved by the institutional review board2930. Clinical stage and histological classification were based on criteria of the International Federation of Gynecology and Obstetrics.…”

“…They also received radiotherapy (30.6 Gy) to the whole pelvis plus additional parametric radiation with central shielding to complete a 50.6 Gy dose, along with 192 Ir high dose-rate intracavitary brachytherapy. Levels of FGF13 expression were analyzed using a streptavidin-biotin immunoperoxidase technique described elsewhere2930. Negative control specimens for all experiments (no primary antibody) were incubated in the same manner at each step.…”