Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness

Waning, David L.; Guise, Theresa A.

doi:10.1158/1078-0432.ccr-13-1590

Cited by 93 publications

(73 citation statements)

References 72 publications

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“…Reviewed in. 17,65 Cancer and muscle weakness DL Waning et al patients should thus have a positive impact on adherence to treatment regimens and overall health. 20 Therefore, a better understanding of the mechanisms of muscle weakness associated with bone metastases and cancer cachexia will lead to improved therapy.…”

Section: Figurementioning

confidence: 99%

Cancer-associated muscle weakness: What's bone got to do with it?

Waning

Guise

2015

BoneKEy Reports

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Cancer-associated muscle weakness is an important paraneoplastic syndrome for which there is currently no treatment. Tumor cells commonly metastasize to bone in advanced cancer to disrupt normal bone remodeling and result in morbidity that includes muscle weakness. Tumor in bone stimulates excessive osteoclast activity, which causes the release of growth factors stored in the mineralized bone matrix. These factors fuel a feed-forward vicious cycle of tumor growth in bone and bone destruction. Recent evidence indicates that these bone-derived growth factors can act systemically to cause muscle weakness. Muscle weakness can be caused by reduced muscle mass or reduced muscle function; in advanced disease, it is likely due to a combination of both reduced quantity and quality of muscle. In this review, we discuss possible mechanisms that lead to skeletal muscle weakness due to bone metastases.

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Section: Figurementioning

confidence: 99%

Cancer-associated muscle weakness: What's bone got to do with it?

Waning

Guise

2015

BoneKEy Reports

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“…33,80 Once in the bone, tumour cells first form micrometastases that can either proliferate and form overt metastatic lesions or remain dormant for long periods until they reactivate and establish tumours. 82 The mechanisms by which some tumour cells remain dormant whereas others are stimulated to proliferate remain to be established. However, amassing evidence suggests that factors that increase bone turnover, including menopause/ovariectomy, may stimulate the cells within the mesenchymal stem cell niche and drive proliferation of dormant tumour cells.…”

Section: Tumour Cell Colonisation and Growth To Bonementioning

confidence: 99%

“…83 Increased proliferation of tumour cells in the bone marrow causes the production of molecules and growth factors by both tumour cells and bone resorption that promote tumour growth, osteoclast production, osteoblast inactivation and bone destruction (osteolysis), a process known as a 'vicious cycle', as shown in Figure 3. 82 More specifically, proliferating cancer cells have been shown to release factors such as parathyroid hormone-related protein (PTHrP), interleukins (IL-8, -11), MMP-1, cyclooxygenase-2 (COX-2), transcription factor GLI2 and HIF-1a that promote both their growth in the bone marrow and osteolysis.…”

Section: Tumour Cell Colonisation and Growth To Bonementioning

confidence: 99%

Molecular alterations that drive breast cancer metastasis to bone

2015

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Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis.

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“…1,2) In osteolysis caused by metastatic cancers including breast cancer and multiple myeloma, the major source of osteolytic alterations in breast cancer bone metastasis has been proposed to be the activation of osteoclasts, [3][4][5] specialized cells that solubilize the bone matrix. 6) An increased activity of osteoclastic bone resorption affects bone mechanical properties, not only by decreasing the bone mass but also by changing the bone structure.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

2016

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Breast cancer is highly metastatic to bone tissue and causes osteolytic lesions through osteoclast activation. Although the effects of osteolytic metastasis on bone quantity have been well studied, whether osteoclast activation induced by cancer bone metastasis affects the bone microstructure, a notable aspect of the bone quality, remains uncertain. The aim of this study was to clarify the effect of osteolytic bone metastasis in breast cancer on the microstructure of the bone matrix, particularly the integrity of collagen bril orientation. Osteolytic breast cancer cells induced hyperactivation of osteoclasts both in vivo and in vitro. Osteoclasts differentiated by culture of monocytes in the cancer cell-derived conditioned medium had an increased number of nuclei; more speci c podosome structures were organized compared to osteoclasts differentiated in the control medium. These observations suggest that the resorptive capacity of a single osteoclast was abnormally upregulated in the cancer-involving environment, causing geometrically irregular resorption cavities. Histological studies on mouse femurs with metastasis of breast cancer MDA-MB-231 cells revealed that the osteoclasts in the metastatic bone were abnormally large and they generated resorption cavities that are irregular both in size and in shape. Notably, collagen matrix in newly formed bone in metastatic bone exhibited a signi cantly disorganized architecture. To the best of our knowledge, this is the rst report demonstrating that osteolytic bone metastasis induces the disruption of bone matrix alignment, which determines the mechanical function of bone in both intact and diseased bone tissue.

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Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness

Cited by 93 publications

References 72 publications

Cancer-associated muscle weakness: What's bone got to do with it?

Cancer-associated muscle weakness: What's bone got to do with it?

Molecular alterations that drive breast cancer metastasis to bone

Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

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