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WO2012158960A2

WO2012158960A2PCT/US2012/038425US2012038425WWO2012158960A2WO 2012158960 A2WO2012158960 A2WO 2012158960A2US 2012038425 WUS2012038425 WUS 2012038425WWO 2012158960 A2WO2012158960 A2WO 2012158960A2

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Abstract

Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease.

The most immediate and pressing concern on receiving a cancer diagnosis is to determine the extent to which it has spread—a process known as cancer metastasis. Metastasis to any organ presents a life-threatening and often incurable disease, yet among the different organs that host metastatic disease, the biology of bone metastasis is perhaps the most exceptional. The first unique aspect is the “reverse hematopoiesis” that takes place; during normal hematopoiesis, hematopoietic stem cells (HSCs) mature into the variety of cell types that form the blood and enter into circulation. During the systemic spread of cancer, this process appears to run in reverse wherein the spongy tissue of the red marrow can collect disseminated tumor cells (DTCs) from nearly any type of cancer (Aguirre-Ghiso 2007) and the nurturing niche that normally hosts HSCs is hijacked by the cancer cells (Shiozawa et al. 2011). This idea is sup

Abstract

Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER tumor, suggesting its preventive use for bone recurrence in ER patients.

Subject terms: Cancer, Breast cancer

Bone metastasis is a major complication of breast cancer (BC) and ER tumors have a higher incidence of bone metastasis than ER tumors. Here, the authors report that miR‐19a in exosomes and the bone matrix protein, IBSP, are upregulated and secreted by bone tropic ER BC cells, where they cooperatively induce osteoclastogenesis and promote bone colonization.

Introduction

Bone metastasis is the most predominant complication of breast cancer. More than 50% of patients have bone as the first site of di