Bone-Derived IGF Mediates Crosstalk between Bone and Breast Cancer Cells in Bony Metastases

Abstract

The continuous release of bone-stored growth factors following bone resorption promotes the colonization of circulating cancer cells. However, the precise role of each of the various growth factors remains unclear. In this study, we investigated the role of bone-derived insulin-like growth factor (IGF) in the development of bone metastases in an animal model of breast cancer. We found that local stimulation of calvarial bone resorption prior to cell inoculation stimulated subsequent bone metastases to that site in vivo, while inhibition of bone resorption inhibited bone metastases. Anchorage-independent growth of cancer cells was stimulated by the culture supernatants from resorbed bones, which contained elevated levels of IGF type I (IGF-1). This stimulation was blocked by IGF-1 receptor (IGF1R) neutralizing antibody, but not antibody targeting other bone-stored growth factors including TGFβ, fibroblast growth factors, and platelet derived growth factors. While recombinant human IGF-I caused IGFIR tyrosine autophosphorylation, followed by activation of Akt and NF-κB in cancer cells, dominant-negative inhibition of IGFIR, Akt, or NF-κB significantly reduced bone metastases with increased apoptosis and decreased mitosis in metastatic cells. Together, our findings suggest that bone-derived IGF-I bridges the crosstalk between bone and metastasized cancer cells via activation of the IGFIR/Akt/NF-κB pathway. Disruption of this pathway therefore may represent a promising therapeutic intervention for bone metastasis.

New therapeutic targets for cancer bone metastasis

“…As for bone metastases, neutralizing antibody against IGF type I receptor (IGF-IR), but not other bone-secreted factors such as TGF-β, fibroblast growth factors (FGFs), and platelet-derived growth factors (PDGFs), blocks breast cancer bone anchorage. This supports a unique and important role of bone-derived IGF-I in the crosstalk between the bone microenvironment and the cancer cells [95]. …”

Insulin-like growth factor receptor-1 (IGF-IR) as a target for prostate cancer therapy

“…Li et al further showed that androgen-deprivation can upregulate VEGF-C expression through down-regulation of the IGF-IR pathway and activate the forkhead transcriptional factor FOXO-1 (74). In bone metastasis, bone-derived IGF-I can bridge the crosstalk between bone and metastasized cancer cells via activation of the IGF-IR/Akt/NF-κB pathway (78). Therefore, disruption of IGF-IR and NK-kB pathways may represent a promising therapeutic intervention for bone metastasis, whereas co-targeting IGF-IR and VEGF may be more effective to treat lymphatic metastasis.…”

Elevated Pentraxin 3 in bone metastatic breast cancer is correlated with osteolytic function

“…Approximately 80% of patients with disseminated metastatic breast cancer develop skeletal metastases [2, 3], emphasizing that breast cancer has a propensity to metastasize to bone. Bone metastases from breast cancer are typically osteolytic and feature bone resorption [4–8]. In the bone microenvironment, breast cancer cells produce osteoclast (OC)-activating cytokines, including parathyroid hormone-related protein (PTH-rP), prostaglandin E 2 (PEG 2 ), and interleukin-11 (IL–11) [5], which can increase expression of receptor activator of nuclear factor-κB ligand (RANKL) by osteoblasts (OBs).…”