Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

Abstract

Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

Keywords: Bone metastasis; Breast neoplasms; Osteoblasts; Osteoclasts; Transforming growth factor beta; Tumor-stromal interaction.

Fig. 1. Tumor-stromal interactions in bone metastasis. Key pathways uncovered by our lab are highlighted, including: (1) vascular cell adhesion molecule 1 (VCAM1) activated osteolytic expansion of indolent bone micrometastasis (left); (2) osteolytic paracrine signaling cascade initiated by matrix metalloproteinase (MMPs, middle); (3) a positive feedback loop in bone metastasis mediated by Jagged1/Notch and transforming growth factor β (TGF-β) signaling pathways (right). See text for details. sVCAM1, soluble vascular cell adhesion molecule 1; CCL2, chemokine (C-C motif) ligand 2; sICAM1, soluble intercellular adhesion molecule 1; IL-11, interleukin 11; CTGF, connective tissue growth factor; ADAMTS1, ADAM metallopeptidase with thrombospondin type 1 motif, 1; HB-EGF, heparinbinding epidermal growth factor-like growth factor; AREG, amphiregulin; EGFR, epidermal growth factor receptor; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor kappa-β; RANKL, receptor activator of nuclear factor kappa-β ligand; Jag1, Jagged1; miRNA, micro RNA; IL-6, interleukin 6.