International Journal of Molecular Sciences

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16 pages, 1766 KiB

Open AccessArticle

The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment

by Mitsuru Futakuchi, Kris Lami, Yuri Tachibana, Yukari Yamamoto, Masahiro Furukawa and Junya Fukuoka

Int. J. Mol. Sci. 2019, 20(20), 5117; https://doi.org/10.3390/ijms20205117 - 15 Oct 2019

Cited by 24 | Viewed by 3822

Abstract

Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary tumor [...] Read more.

Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria and into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ micro-Es. After implantation of the tumor cells, mice were treated with a TGF-β R1 kinase inhibitor (R1-Ki). Results: Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone micro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis or apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers, SOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E. R1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone micro-E but not in the subQ micro-E. TGF-β activation of the MAPK/ERK and AKT pathways was the underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role in cell proliferation in either micro-E. Conclusion: Our results indicated that the bone micro-E is a key niche for CSC generation, and TGF-β signaling has important roles in generating CSCs and tumor cell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to chemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor microenvironments in vivo. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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14 pages, 2352 KiB

Open AccessArticle

Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis

by Marineta Kovacheva, Michael Zepp, Muriel Schraad, Stefan Berger and Martin R. Berger

Int. J. Mol. Sci. 2019, 20(19), 4918; https://doi.org/10.3390/ijms20194918 - 4 Oct 2019

Cited by 24 | Viewed by 3658

Abstract

High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is [...] Read more.

High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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13 pages, 1435 KiB

Open AccessArticle

CXCR2: A Novel Mediator of Mammary Tumor Bone Metastasis

by Bhawna Sharma, Kalyan C. Nannuru, Sugandha Saxena, Michelle L. Varney and Rakesh K. Singh

Int. J. Mol. Sci. 2019, 20(5), 1237; https://doi.org/10.3390/ijms20051237 - 12 Mar 2019

Cited by 13 | Viewed by 4131

Abstract

Most breast cancer patients die due to bone metastasis. Although metastasis accounts for 5% of the breast cancer cases, it is responsible for most of the deaths. Sometimes even before the detection of a primary tumor, most of the patients have bone and [...] Read more.

Most breast cancer patients die due to bone metastasis. Although metastasis accounts for 5% of the breast cancer cases, it is responsible for most of the deaths. Sometimes even before the detection of a primary tumor, most of the patients have bone and lymph node metastasis. Moreover, at the time of death, breast cancer patients have the bulk of the tumor burden in their bones. Therapy options are available for the treatment of primary tumors, but there are minimal options for treating breast cancer patients who have bone metastasis. C-X-C motif chemokine receptor type 2 (CXCR2) receptor-mediated signaling has been shown to play a critical role during bone-related inflammations and its ligands C-X-C motif chemokine ligand 6 (CXCL6) and 8 (CXCL8) aid in the resorption of bone during bone metastasis. In this study, we tested the hypothesis that CXCR2 contributes to mammary tumor-induced osteolysis and bone metastasis. In the present study, we examined the role of both tumor cell-derived and host-derived CXCR2 in influencing mammary tumor cell bone metastasis. For understanding the role of tumor cell-derived CXCR2, we utilized Cl66 CXCR2 knockdown (Cl66-shCXCR2) and Cl66-Control cells (Cl66-Control) and observed a significant decrease in tumor growth and tumor-induced osteolysis in Cl66-shCXCR2 cells in comparison with the Cl66-Control cells. Next, for understanding the role of host-derived CXCR2, we utilized mice with genomic knockdown of CXCR2 (Cxcr2^−/−) and injected Cl66-Luciferase (Cl66-Luc) or 4T1-Luciferase (4T1-Luc) cells. We observed decreased bone destruction and metastasis in the bone of Cxcr2^−/− mice. Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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14 pages, 12519 KiB

Open AccessArticle

Pericytes as a Source of Osteogenic Cells in Bone Fracture Healing

by Sopak Supakul, Kenta Yao, Hiroki Ochi, Tomohito Shimada, Kyoko Hashimoto, Satoko Sunamura, Yo Mabuchi, Miwa Tanaka, Chihiro Akazawa, Takuro Nakamura, Atsushi Okawa, Shu Takeda and Shingo Sato

Int. J. Mol. Sci. 2019, 20(5), 1079; https://doi.org/10.3390/ijms20051079 - 2 Mar 2019

Cited by 58 | Viewed by 11014

Abstract

Pericytes are mesenchymal cells that surround the endothelial cells of small vessels in various organs. These cells express several markers, such as NG2, CD146, and PDGFRβ, and play an important role in the stabilization and maturation of blood vessels. It was also recently [...] Read more.

Pericytes are mesenchymal cells that surround the endothelial cells of small vessels in various organs. These cells express several markers, such as NG2, CD146, and PDGFRβ, and play an important role in the stabilization and maturation of blood vessels. It was also recently revealed that like mesenchymal stem cells (MSCs), pericytes possess multilineage differentiation capacity, especially myogenic, adipogenic, and fibrogenic differentiation capacities. Although some previous studies have reported that pericytes also have osteogenic potential, the osteogenesis of pericytes can still be further elucidated. In the present study, we established novel methods for isolating and culturing primary murine pericytes. An immortalized pericyte line was also established. Multilineage induction of the pericyte line induced osteogenesis, adipogenesis, and chondrogenesis of the cells in vitro. In addition, pericytes that were injected into the fracture site of a bone fracture mouse model contributed to callus formation. Furthermore, in vivo pericyte-lineage-tracing studies demonstrated that endogenous pericytes also differentiate into osteoblasts and osteocytes and contribute to bone fracture healing as a cellular source of osteogenic cells. Pericytes can be a promising therapeutic candidate for treating bone fractures with a delayed union or nonunion as well as bone diseases causing bone defects. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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Review

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37 pages, 2121 KiB

Open AccessReview

The Regulation of Bone Metabolism and Disorders by Wnt Signaling

by Kazuhiro Maeda, Yasuhiro Kobayashi, Masanori Koide, Shunsuke Uehara, Masanori Okamoto, Akihiro Ishihara, Tomohiro Kayama, Mitsuru Saito and Keishi Marumo

Int. J. Mol. Sci. 2019, 20(22), 5525; https://doi.org/10.3390/ijms20225525 - 6 Nov 2019

Cited by 239 | Viewed by 22517

Abstract

Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical [...] Read more.

Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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16 pages, 890 KiB

Open AccessReview

The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis

by Mari I. Suominen, Timothy Wilson, Sanna-Maria Käkönen and Arne Scholz

Int. J. Mol. Sci. 2019, 20(16), 3899; https://doi.org/10.3390/ijms20163899 - 10 Aug 2019

Cited by 23 | Viewed by 5298

Abstract

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. [...] Read more.

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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22 pages, 1292 KiB

Open AccessReview

New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?

by Geoffroy Danieau, Sarah Morice, Françoise Rédini, Franck Verrecchia and Bénédicte Brounais-Le Royer

Int. J. Mol. Sci. 2019, 20(15), 3751; https://doi.org/10.3390/ijms20153751 - 31 Jul 2019

Cited by 65 | Viewed by 6194

Abstract

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for [...] Read more.

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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16 pages, 821 KiB

Open AccessReview

Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases

by Taiwo Samuel Agidigbi and Chaekyun Kim

Int. J. Mol. Sci. 2019, 20(14), 3576; https://doi.org/10.3390/ijms20143576 - 22 Jul 2019

Cited by 308 | Viewed by 12382

Abstract

Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to [...] Read more.

Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O₂⁻) and hydrogen peroxide (H₂O₂), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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22 pages, 1859 KiB

Open AccessReview

Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy

by Jeremy S. Frieling and Conor C. Lynch

Int. J. Mol. Sci. 2019, 20(11), 2814; https://doi.org/10.3390/ijms20112814 - 8 Jun 2019

Cited by 8 | Viewed by 8302

Abstract

Parathyroid hormone-related protein (PTHrP), with isoforms ranging from 139 to 173 amino acids, has long been implicated in the development and regulation of multiple tissues, including that of the skeleton, via paracrine and autocrine signaling. PTHrP is also known as a potent mediator [...] Read more.

Parathyroid hormone-related protein (PTHrP), with isoforms ranging from 139 to 173 amino acids, has long been implicated in the development and regulation of multiple tissues, including that of the skeleton, via paracrine and autocrine signaling. PTHrP is also known as a potent mediator of cancer-induced bone disease, contributing to a vicious cycle between tumor cells and the bone microenvironment that drives the formation and progression of metastatic lesions. The abundance of roles ascribed to PTHrP have largely been attributed to the N-terminal 1–36 amino acid region, however, activities for mid-region and C-terminal products as well as additional shorter N-terminal species have also been described. Studies of the protein sequence have indicated that PTHrP is susceptible to post-translational proteolytic cleavage by multiple classes of proteases with emerging evidence pointing to novel functional roles for these PTHrP products in regulating cell behavior in homeostatic and pathological contexts. As a consequence, PTHrP products are also being explored as potential biomarkers of disease. Taken together, our enhanced understanding of the post-translational regulation of PTHrP bioactivity could assist in developing new therapeutic approaches that can effectively treat skeletal malignancies. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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15 pages, 473 KiB

Open AccessReview

Hypoxic Microenvironment and Metastatic Bone Disease

by Toru Hiraga

Int. J. Mol. Sci. 2018, 19(11), 3523; https://doi.org/10.3390/ijms19113523 - 9 Nov 2018

Cited by 58 | Viewed by 6280

Abstract

Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible [...] Read more.

Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible factors, which play critical roles in the key stages of metastatic dissemination including angiogenesis, epithelial-mesenchymal transition, invasion, maintenance of cancer stem cells, tumor cell dormancy, release of extracellular vesicles, and generation of pre-metastatic niches. Hypoxia also affects bone cells, such as osteoblasts and osteoclasts, and immune cells, which also act to support the development and progression of bone metastases. Paradoxically, hypoxia and related signaling molecules are recognized as high-priority therapeutic targets and many candidate drugs are currently under preclinical and clinical investigation. The present review focuses on our current knowledge of the potential roles of hypoxia in cancer metastasis to bone by considering the interaction between metastatic cancer cells and the bone microenvironment. Current therapeutic approaches targeting hypoxia are also described. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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18 pages, 1041 KiB

Open AccessReview

Mesenchymal Stem Cell Migration during Bone Formation and Bone Diseases Therapy

by Peihong Su, Ye Tian, Chaofei Yang, Xiaoli Ma, Xue Wang, Jiawei Pei and Airong Qian

Int. J. Mol. Sci. 2018, 19(8), 2343; https://doi.org/10.3390/ijms19082343 - 9 Aug 2018

Cited by 171 | Viewed by 11975

Abstract

During bone modeling, remodeling, and bone fracture repair, mesenchymal stem cells (MSCs) differentiate into chondrocyte or osteoblast to comply bone formation and regeneration. As multipotent stem cells, MSCs were used to treat bone diseases during the past several decades. However, most of these [...] Read more.

During bone modeling, remodeling, and bone fracture repair, mesenchymal stem cells (MSCs) differentiate into chondrocyte or osteoblast to comply bone formation and regeneration. As multipotent stem cells, MSCs were used to treat bone diseases during the past several decades. However, most of these implications just focused on promoting MSC differentiation. Furthermore, cell migration is also a key issue for bone formation and bone diseases treatment. Abnormal MSC migration could cause different kinds of bone diseases, including osteoporosis. Additionally, for bone disease treatment, the migration of endogenous or exogenous MSCs to bone injury sites is required. Recently, researchers have paid more and more attention to two critical points. One is how to apply MSC migration to bone disease therapy. The other is how to enhance MSC migration to improve the therapeutic efficacy of bone diseases. Some considerable outcomes showed that enhancing MSC migration might be a novel trick for reversing bone loss and other bone diseases, such as osteoporosis, fracture, and osteoarthritis (OA). Although plenty of challenges need to be conquered, application of endogenous and exogenous MSC migration and developing different strategies to improve therapeutic efficacy through enhancing MSC migration to target tissue might be the trend in the future for bone disease treatment. Full article

(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)

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