Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness

Hesse, Eric; Schröder, Saskia; Brandt, Diana; Pamperin, Jenny; Saito, Hiroaki; Taipaleenmäki, Hanna

doi:10.1172/jci.insight.125543

Cited by 84 publications

(79 citation statements)

References 48 publications

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“…Similarly, the bone anabolic and anti-resorptive effect of Scl-Ab was recently demonstrated in a pre-clinical mouse model of bone metastases (55). Importantly, Scl-Ab treatment not only reduced metastatic breast cancer burden in vivo but also protected from cancer-induced bone and muscle loss and increased survival of cancer-bearing animals (55). In addition, further agents targeting osteoblast differentiation and function have been investigated for the treatment of bone metastasis in various cancers, with potential benefits also for breast cancer-induced bone disease (41).…”

Section: Osteoblasts As Novel Target To Treat Bone Metastases-bone Anmentioning

confidence: 70%

“…In clinical trials, sclerostin antibody treatment of women with postmenopausal osteoporosis increased bone formation, while bone resorption was decreased, leading to an increase in bone mineral density and a reduction of the fracture rate at several sites, including the hip and spine (54). Similarly, the bone anabolic and anti-resorptive effect of Scl-Ab was recently demonstrated in a pre-clinical mouse model of bone metastases (55). Importantly, Scl-Ab treatment not only reduced metastatic breast cancer burden in vivo but also protected from cancer-induced bone and muscle loss and increased survival of cancer-bearing animals (55).…”

Section: Osteoblasts As Novel Target To Treat Bone Metastases-bone Anmentioning

confidence: 95%

“…Nevertheless, recently published studies highlight their potential as novel cellular targets to prevent and/or treat breast cancer bone metastasis (7,8,29,34,38,39,75). In addition, the therapeutic importance of osteoblasts has been acknowledged with novel therapeutics including bone anabolic agents such as PTH and anti-sclerostin antibody (51,55). However, a detailed characterization of how bone anabolic agents modify the composition and/or location of the endosteal niche as well as potential consequences on tumor cell colonization and metastatic outgrowth remains to be performed.…”

Section: Conclusion/perspectivementioning

confidence: 99%

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The Endosteal Niche in Breast Cancer Bone Metastasis

2020

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The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in "metastatic niches," special microenvironments that are thought to regulate cancer cell colonization and dormancy as well as tumor progression and subsequent development into overt metastases. Precise location and composition of this "metastatic niche" remain poorly defined. However, it is thought to include an "endosteal niche" that is composed of key bone cells that are derived from both, hematopoietic stem cells (osteoclasts), and mesenchymal stromal cells (osteoblasts, fibroblasts, adipocytes). Our knowledge of how osteoclasts drive the late stage of the disease is well-established. In contrast, much less is known about the interaction between osteogenic cells and disseminated tumor cells prior to the initiation of the osteolytic phase. Recent studies suggest that mesenchymal-derived cells, including osteoblasts and fibroblasts, play a key role during the early stages of breast cancer bone metastasis such as tumor cell homing, bone marrow colonization, and tumor cell dormancy. Hence, elucidating the interactions between breast cancer cells and mesenchymal-derived cells that drive metastasis progression could provide novel therapeutic approaches and targets to treat breast cancer bone metastasis. In this review we discuss evidences reporting the interaction between tumor cells and endosteal niche cells during the early stages of breast cancer bone metastasis, with a particular focus on mesenchymal-derived osteoblasts and fibroblasts.

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Section: Osteoblasts As Novel Target To Treat Bone Metastases-bone Anmentioning

confidence: 70%

Section: Osteoblasts As Novel Target To Treat Bone Metastases-bone Anmentioning

confidence: 95%

Section: Conclusion/perspectivementioning

confidence: 99%

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The Endosteal Niche in Breast Cancer Bone Metastasis

2020

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“…The Wnt antagonist sclerostin is secreted by osteocytes in the bone marrow and inhibits new bone formation by binding to low-density lipoprotein receptor 5 (LRP-5) on osteoblasts. Promising preclinical data have demonstrated a reduced metastatic breast cancer burden in the bones of female immune-compromised SCID mice, in addition to a prolonged survival upon treatment with anti-sclerostin antibody [115]. In addition, anti-sclerostin antibody treatment prevented breast cancer-induced bone loss by enhancing osteoblast function and simultaneously inhibiting bone resorption.…”

Section: The Bone Marrow Microenvironment As a Target To Treat Breastmentioning

confidence: 99%

Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment

et al. 2020

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Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteoclasts in breast cancer bone metastases is well established, the function of other bone cells, as well as adipocytes, endothelial cells, and nerve cells is less understood. In this review, we discuss the composition of the physiological bone microenvironment and how the presence of tumor cells influences the microenvironment, creating a pathological crosstalk between the cells. A better understanding of the cellular and molecular events that occur in the metastatic bone microenvironment could facilitate the identification of novel cellular targets to treat this devastating disease.

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“…Sclerostin is a Wnt signaling antagonist secreted by osteocytes, inhibiting osteoblastogenesis and new bone formation. Preclinical studies have shown a decreasing metastatic breast cancer burden in the mice bones with anti-sclerostin treatment ( 157 ). Interestingly, anti-sclerostin also reduces the volume of BMAs ( 158 ), implicating that the antitumor effect of sclerostin antibody may partly attribute to inhibiting BMAs ( 7 ).…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer

Liu

Zhao

2020

Front. Oncol.

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Accumulating discoveries highlight the importance of interaction between marrow stromal cells and cancer cells for bone metastasis. Bone is the most common metastatic site of breast cancer and bone marrow adipocytes (BMAs) are the most abundant component of the bone marrow microenvironment. BMAs are unique in their origin and location, and recently they are found to serve as an endocrine organ that secretes adipokines, cytokines, chemokines, and growth factors. It is reasonable to speculate that BMAs contribute to the modification of bone metastatic microenvironment and affecting metastatic breast cancer cells in the bone marrow. Indeed, BMAs may participate in bone metastasis of breast cancer through regulation of recruitment, invasion, survival, colonization, proliferation, angiogenesis, and immune modulation by their production of various adipocytokines. In this review, we provide an overview of research progress, focusing on adipocytokines secreted by BMAs and their potential roles for bone metastasis of breast cancer, and investigating the mechanisms mediating the interaction between BMAs and metastatic breast cancer cells. Based on current findings, BMAs may function as a pivotal modulator of bone metastasis of breast cancer, therefore targeting BMAs combined with conventional treatment programs might present a promising therapeutic option.

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Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness

Cited by 84 publications

References 48 publications

The Endosteal Niche in Breast Cancer Bone Metastasis

The Endosteal Niche in Breast Cancer Bone Metastasis

Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment

Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer

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