Breast cancer cell-derived fibroblast growth factors enhance osteoclast activity and contribute to the formation of metastatic lesions

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in promoting breast cancer growth and progression. While the autocrine effects of FGFR activation in tumor cells have been extensively studied, little is known about the effects of tumor cell-derived FGFs on cells in the microenvironment. Because FGF signaling has been implicated in the regulation of bone formation and osteoclast differentiation, we hypothesized that tumor cell-derived FGFs are capable of modulating osteoclast function and contributing to growth of metastatic lesions in the bone. Initial studies examining FGFR expression during osteoclast differentiation revealed increased expression of FGFR1 in osteoclasts during differentiation. Therefore, studies were performed to determine whether tumor cell-derived FGFs are capable of promoting osteoclast differentiation and activity. Using both non-transformed and transformed cell lines, we demonstrate that breast cancer cells express a number of FGF ligands that are known to activate FGFR1. Furthermore our results demonstrate that inhibition of FGFR activity using the clinically relevant inhibitor BGJ398 leads to reduced osteoclast differentiation and activity in vitro. Treatment of mice injected with tumor cells into the femurs with BGJ398 leads to reduced osteoclast activity and bone destruction. Together, these studies demonstrate that tumor cell-derived FGFs enhance osteoclast function and contribute to the formation of metastatic lesions in breast cancer.

Dovitinib dilactic acid reduces tumor growth and tumor-induced bone changes in an experimental breast cancer bone growth model

“…Similar findings were also reported by Aukes et al, who did not observe a decrease in tumor growth by bioluminescence imaging with the FGFR inhibitor BGJ398, but observed an increased bone volume in a model where breast cancer cells were injected into the femur [10]. They also showed that the treatment had no effect on sham-operated bones [10]. In our study, we observed lower serum TRACP5b levels in dovitinib-treated mice indicating that the systemic number of osteoclasts was decreased.…”

“…Lee et al showed that dovitinib enhances osteoblast differentiation in vitro by increasing the expression of osteoblast target genes [14]. The results by Aukes et al suggest that FGFR inhibitor BGJ398 alone has no effect on resorption activity of osteoclasts in vivo [10].…”

Targeting the RANKL/RANK/OPG Axis for Cancer Therapy

“…In a murine model of melanoma metastasis, it was found that for malignant tumors with RANK expression, RANKL produced by osteoblasts and bone marrow stromal cells could act as a chemical attractant and promote the migration and metastasis of malignant tumors to these sites ( 132 ). Similar effects were also found in malignant tumors such as breast cancer ( 97 , 133 – 135 ), prostate cancer ( 136 – 138 ), and lung cancer ( 100 , 104 , 139 ). The activation of phospholipase C (PLC), protein kinase C (PKC), ERK, and phosphatidylinositol-3-OH kinase (PI(3)K) pathways were involved in RANK-induced tumor cell migration ( 140 – 143 ).…”

A Selective FGFR inhibitor AZD4547 suppresses RANKL/M-CSF/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment

“…In a similar context, Aukes et al . demonstrated that the supernatant of MDA-MB-231-derived bone metastasis clones induced osteoclastogenesis 25 . Unlike our approach, they used the cell culture media as a source for tumour-derived FGF and evaluated the effect of FGFR TKI on osteoclastogenesis.…”