New therapeutic targets for cancer bone metastasis

Krzeszinski, Jing Y.; Wan, Yihong

doi:10.1016/j.tips.2015.04.006

Cited by 70 publications

(82 citation statements)

References 156 publications

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“…Remodelling is regulated by the co‐ordinated actions of osteoclasts, which resorb bone, and osteoblasts, which form new mineralized bone. Pathological bone loss occurs when the homeostatic relationship between osteoblasts and osteoclasts is disturbed in favour of osteoclast overactivation or lack of balancing osteoblast activity .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐inducible factor 1‐alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl‐4‐hydroxylase 2

Hulley

Bishop

Vernet

et al. 2017

The Journal of Pathology

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Osteogenic–angiogenic coupling is promoted by the hypoxia‐inducible factor 1‐alpha (HIF‐1α) transcription factor, provoking interest in HIF activation as a therapeutic strategy to improve osteoblast mineralization and treat pathological osteolysis. However, HIF also enhances the bone‐resorbing activity of mature osteoclasts. It is therefore essential to determine the full effect(s) of HIF on both the formation and the bone‐resorbing function of osteoclasts in order to understand how they might respond to such a strategy. Expression of HIF‐1α mRNA and protein increased during osteoclast differentiation from CD14+ monocytic precursors, additionally inducing expression of the HIF‐regulated glycolytic enzymes. However, HIF‐1α siRNA only moderately affected osteoclast differentiation, accelerating fusion of precursor cells. HIF induction by inhibition of the regulatory prolyl‐4‐hydroxylase (PHD) enzymes reduced osteoclastogenesis, but was confirmed to enhance bone resorption by mature osteoclasts. Phd2 +/− murine osteoclasts also exhibited enhanced bone resorption, associated with increased expression of resorption‐associated Acp5, in comparison with wild‐type cells from littermate controls. Phd3 −/− bone marrow precursors displayed accelerated early fusion, mirroring results with HIF‐1α siRNA. In vivo, Phd2 +/− and Phd3 −/− mice exhibited reduced trabecular bone mass, associated with reduced mineralization by Phd2 +/− osteoblasts. These data indicate that HIF predominantly functions as a regulator of osteoclast‐mediated bone resorption, with little effect on osteoclast differentiation. Inhibition of HIF might therefore represent an alternative strategy to treat diseases characterized by pathological levels of osteolysis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

Hypoxia‐inducible factor 1‐alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl‐4‐hydroxylase 2

Hulley

Bishop

Vernet

et al. 2017

The Journal of Pathology

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“…Metastatic breast cancer is the second leading cause of cancer deaths following lung cancer . The process of metastasis is initiated with (i) epithelial‐to‐mesenchymal transition (EMT) of the tumor at the primary site, (ii) extracellular matrix degradation, (iii) intravasation, (iv) migration, (v) evasion from host cell defense mechanism, and (vi) extravasation followed by attachment to the distant metastatic site . The cell surface integrins expressed on tumor cells are vital for attachment of metastasizing cells to other organs.…”

Section: Introductionmentioning

confidence: 99%

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

Sundaram

Kucharski

Parmar

et al. 2017

Macromolecular Bioscience

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Cell surface integrins, which play important roles in the survival, proliferation, migration, and invasion of cancer cells, are a viable target for treatment of metastatic breast cancer. This line of therapy still remains challenging due to the lack of proper identification and validation of effective targets as well as the lack of suitable therapeutic agents for treatment. The focus is on one such molecular target for this purpose, namely integrin-β1, and effective lowering of integrin-β1 levels on a breast cancer model (MDA-MB-231 cells) is achieved by delivering a dicer-substrate short interfering RNA (siRNA) targeting integrin-β1 with lipid-modified low molecular weight polyethylenimine polymers. Reduction of integrin-β1 levels leads to reduced adhesion of MDA-MB-231 cells to extracellular matrix component fibronectin as well as to human bone marrow cells. A reduced migration of the breast cancer cells is also observed after integrin-β1 silencing in "scratch" and "transwell" migration assays. These results highlight the importance of integrin-β1 for the migration of metastatic breast cancer cells by effectively silencing this target with a practical dose of siRNA.

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“…[15,16] Additionally, these metastases cause cancer-associated pain, which is one of the most distressing features of cancer. In the present study, we examined whether there is a commonality in the mechanism of bone resorption and lysis that occur in a diverse set of bone metastatic lesions, as well as in primary bone lesions.…”

Section: Introductionmentioning

confidence: 99%

Dickkopf-1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions

Wang

Zhang

et al. 2016

Medicine

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Recently, an inverse role for Wnt signaling in the development of osteoclasts in the bone was demonstrated. In the present study, we examined whether there is a commonality in the mechanism of bone resorption and lysis that occur in a diverse set of bone metastatic lesions, as well as in primary bone lesions. Compared with control bone tissue and bone biopsies from patients with nonmetastatic primary tumors (i.e., breast carcinoma, lung adenocarcinoma, and prostate carcinoma), patients with bone metastatic lesions from the three aforementioned primary tumors, as well as osteolytic lesions obtained from the bone biopsies of patients with multiple myeloma, demonstrated an upregulated expression of the glycoprotein Dickkopf-1 at both the mRNA and protein levels. Additionally, by coimmunoprecipitation, Dickkopf-1 pulled-down low-density lipoprotein receptor-related protein 6 (Lrp6), which is a key downstream effector of the Wnt signaling pathway. The expression of Lrp6 was unaltered in the osteometastatic lesions. This negative regulation was associated with a lowered expression of osteoprotegerin in the osteometastatic lesions, an observation that was previously reported to promote osteoclastogenesis. These findings provide a common mechanism for the inverse relationship between the Wnt signaling pathway and the development of primary or metastatic bone lesions. Pharmacological modulation of the Wnt signaling pathway might benefit the clinical management of primary and metastatic bone lesions.

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New therapeutic targets for cancer bone metastasis

Cited by 70 publications

References 156 publications

Hypoxia‐inducible factor 1‐alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl‐4‐hydroxylase 2

Hypoxia‐inducible factor 1‐alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl‐4‐hydroxylase 2

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

Dickkopf-1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions

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