Special Issue "Targeting Bone Metastasis in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 April 2018)

Special Issue Editor

Guest Editor
Dr. Yusuke Shiozawa

Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA
Website | E-Mail
Interests: bone metastasis, cancer-induced bone pain, cancer-associated cachexia

Special Issue Information

Dear Colleagues,

Once cancer metastasizes to bone, the mortality rate of patients increases significantly. It has been appreciated that host microenvironment actively influences cancer cells, leading to progressive and incurable bone metastasis, full understanding of the mechanisms involved in bone metastasis remains unknown. It has been suggested that the interactions among cancer cells, tumor microenvironment (e.g., immune cells, cells involved in bone remodeling, stromal fibroblasts), and factors produced by these host cells (e.g., growth factors, cytokines, chemokines, microRNAs) control bone metastatic process. Greater understanding of these interactions will therefore lead us to a better understanding of bone metastatic progression and enable us to pursue innovative and important directions toward treatments.

We invite authors to submit original articles and review articles that seek to explore the interaction between bone metastatic cancer cells and their microenvironment. We are particularly interested in articles describing new insights into the function and morphology of the microenvironment that controls bone metastatic progression.

Potential topics include, but are not limited to:

  •  Identification of factors derived from the tumor microenvironment which influence bone metastatic process
  • The roles of the bone marrow microenvironment in the progression of bone metastasis
  • The participation of the nervous system in the development of bone metastasis
  • Innovative model systems to test and understand the molecular mechanisms of bone metastasis
  • Status of biomaterial-based approaches to reveal the mechanisms of bone metastasis
  • The gap between major clinical problems and basic research in bone metastasis
  • The current situation of treatment for bone metastasis

Dr. Yusuke Shiozawa
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (11 papers)

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Research

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Open AccessArticle Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions
Cancers 2018, 10(12), 463; https://doi.org/10.3390/cancers10120463
Received: 23 October 2018 / Revised: 5 November 2018 / Accepted: 21 November 2018 / Published: 22 November 2018
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Abstract
The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we [...] Read more.
The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2LysMCre KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2LysMCre KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/β-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-β signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessArticle Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone
Cancers 2018, 10(11), 438; https://doi.org/10.3390/cancers10110438
Received: 28 September 2018 / Revised: 2 November 2018 / Accepted: 9 November 2018 / Published: 13 November 2018
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Abstract
The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence [...] Read more.
The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγnull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessArticle Three-Dimensional In Vitro Hydro- and Cryogel-Based Cell-Culture Models for the Study of Breast-Cancer Metastasis to Bone
Cancers 2018, 10(9), 292; https://doi.org/10.3390/cancers10090292
Received: 18 July 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 27 August 2018
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Abstract
Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models [...] Read more.
Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models provide valuable tools to investigate distinct heterocellular and environmental interactions, sophisticated organ-specific metastasis models are lacking. Previous models used to investigate breast-to-bone metastasis have relied on 2.5D or singular-scaffold methods, constraining the in situ mimicry of in vitro models. Glycosaminoglycan-based gels have demonstrated outstanding potential for tumor-engineering applications. Here, we developed advanced biphasic in vitro microenvironments that mimic breast-tumor tissue (MCF-7 and MDA-MB-231 in a hydrogel) spatially separated with a mineralized bone construct (human primary osteoblasts in a cryogel). These models allow distinct advantages over former models due to the ability to observe and manipulate cellular migration towards a bone construct. The gels allow for the binding of adhesion-mediating peptides and controlled release of signaling molecules. Moreover, mechanical and architectural properties can be tuned to manipulate cell function. These results demonstrate the utility of these biomimetic microenvironment models to investigate heterotypic cell–cell and cell–matrix communications in cancer migration to bone. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessArticle Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation
Cancers 2018, 10(6), 190; https://doi.org/10.3390/cancers10060190
Received: 13 April 2018 / Revised: 22 May 2018 / Accepted: 6 June 2018 / Published: 8 June 2018
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Abstract
MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone [...] Read more.
MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Review

Jump to: Research

Open AccessReview The Osteoclast in Bone Metastasis: Player and Target
Cancers 2018, 10(7), 218; https://doi.org/10.3390/cancers10070218
Received: 1 June 2018 / Revised: 21 June 2018 / Accepted: 21 June 2018 / Published: 27 June 2018
Cited by 5 | PDF Full-text (4800 KB) | HTML Full-text | XML Full-text
Abstract
Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers [...] Read more.
Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers in the field. The bone is a heterogeneous environment that represents a fertile soil for tumor cells, supporting their growth. Among the different cell types present in the bone, in this review we will focus our attention on the osteoclasts, which are crucial players in the so called “vicious cycle”, a phenomenon triggered by tumor cells eventually leading to both tumor proliferation as well as bone deregulation, thus fueling the development of bone metastasis. The complex network, linking tumor cells to the bone by activating osteoclasts, represents a fruitful target for the treatment of bone metastases. In this review we will describe how tumor cells perturb the bone microenvironment by actively influencing osteoclast formation and activity. Moreover, we will describe the current antiresorptive drugs employed in the treatment of bone metastases as well as new, targeted therapies able to affect both cancer cells and osteoclasts. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessFeature PaperReview Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis
Cancers 2018, 10(6), 185; https://doi.org/10.3390/cancers10060185
Received: 30 April 2018 / Revised: 31 May 2018 / Accepted: 1 June 2018 / Published: 5 June 2018
Cited by 2 | PDF Full-text (1308 KB) | HTML Full-text | XML Full-text
Abstract
Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are [...] Read more.
Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose role in cancer has been widely documented. They are capable of contributing to every step of the metastatic cascade, but enthusiasm for the use of MMP inhibition as a therapeutic approach has been dampened by the disappointing results of clinical trials conducted more than 20 years ago. Since the trials, our knowledge of MMP biology has expanded greatly. Combined with advances in the selective targeting of individual MMPs and the specific delivery of therapeutics to the tumor microenvironment, we may be on the verge of finally realizing the promise of MMP inhibition as a treatment strategy. Here, as a case in point, we focus specifically on MMP-2 as an example to show how it can contribute to each stage of breast-cancer-to-bone metastasis and also discuss novel approaches for the selective targeting of MMP-2 in the setting of the bone-cancer microenvironment. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessReview Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts
Cancers 2018, 10(6), 182; https://doi.org/10.3390/cancers10060182
Received: 4 April 2018 / Revised: 29 May 2018 / Accepted: 31 May 2018 / Published: 4 June 2018
Cited by 1 | PDF Full-text (3829 KB) | HTML Full-text | XML Full-text
Abstract
The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between [...] Read more.
The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessFeature PaperReview Emerging and Established Models of Bone Metastasis
Cancers 2018, 10(6), 176; https://doi.org/10.3390/cancers10060176
Received: 17 April 2018 / Revised: 30 May 2018 / Accepted: 30 May 2018 / Published: 1 June 2018
Cited by 4 | PDF Full-text (536 KB) | HTML Full-text | XML Full-text
Abstract
Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. Bone is the primary site of metastasis for several cancers—breast and prostate cancers in particular. Efforts to treat bone metastases have been stymied by a lack [...] Read more.
Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. Bone is the primary site of metastasis for several cancers—breast and prostate cancers in particular. Efforts to treat bone metastases have been stymied by a lack of models to study the progression, cellular players, and signaling pathways driving bone metastasis. In this review, we examine newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic, and in silico computational bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cells enter and then escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessReview Multidisciplinary Approach for Bone Metastasis: A Review
Cancers 2018, 10(6), 156; https://doi.org/10.3390/cancers10060156
Received: 23 March 2018 / Revised: 22 May 2018 / Accepted: 23 May 2018 / Published: 24 May 2018
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Abstract
Progress in cancer treatment has improved the survival of patients with advanced-stage cancers. Consequently, the clinical courses of patients are prolonged and often accompanied by morbidity due to bone metastases. Skeletal-related events (SREs), such as pathological fractures and spinal paralysis, cause impairment in [...] Read more.
Progress in cancer treatment has improved the survival of patients with advanced-stage cancers. Consequently, the clinical courses of patients are prolonged and often accompanied by morbidity due to bone metastases. Skeletal-related events (SREs), such as pathological fractures and spinal paralysis, cause impairment in activities of daily life and quality of life (QOL). To avoid serious SREs causing impairment in QOL and survival, early diagnosis and a prophylactic approach are required. It is necessary to initiate a bone management program concurrently with the initiation of cancer treatment to prevent complications of bone metastasis. In addition, the requirement of a multidisciplinary approach through a cancer board focusing on the management of bone metastases and involving a team of specialists in oncology, palliative care, radiotherapy, orthopedics, nuclear medicine, radiology, and physiatrists has been emphasized. In the cancer board, a strong focus is placed on the prevention of complications due to bone metastases and on reductions in the high morbidity, hospitalization rate, and overall costs associated with advanced-stage cancers. Recent reports suggest the usefulness of such approaches. The multidisciplinary approach through a cancer board would improve QOL and prognosis of patients, leading to new or continued systemic therapy for primary cancers. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessFeature PaperReview Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases
Cancers 2018, 10(5), 141; https://doi.org/10.3390/cancers10050141
Received: 17 April 2018 / Revised: 7 May 2018 / Accepted: 8 May 2018 / Published: 10 May 2018
Cited by 2 | PDF Full-text (928 KB) | HTML Full-text | XML Full-text
Abstract
Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe [...] Read more.
Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe side effects as well as the risk of abuse and addiction. Therefore, alternative treatments for CIBP are desperately needed. Although the exact mechanisms of CIBP have not been fully elucidated, recent studies using preclinical models have demonstrated the role of the bone marrow microenvironment (e.g., osteoclasts, osteoblasts, macrophages, mast cells, mesenchymal stem cells, and fibroblasts) in CIBP development. Several clinical trials have been performed based on these findings. CIBP is a complex and challenging condition that currently has no standard effective treatments other than opioids. Further studies are clearly warranted to better understand this painful condition and develop more effective and safer targeted therapies. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Open AccessReview Cancer Stem Cells, Bone and Tumor Microenvironment: Key Players in Bone Metastases
Received: 5 December 2017 / Revised: 12 February 2018 / Accepted: 17 February 2018 / Published: 20 February 2018
Cited by 7 | PDF Full-text (615 KB) | HTML Full-text | XML Full-text
Abstract
Tumor mass is constituted by a heterogeneous group of cells, among which a key role is played by the cancer stem cells (CSCs), possessing high regenerative properties. CSCs directly metastasize to bone, since bone microenvironment represents a fertile environment that protects CSCs against [...] Read more.
Tumor mass is constituted by a heterogeneous group of cells, among which a key role is played by the cancer stem cells (CSCs), possessing high regenerative properties. CSCs directly metastasize to bone, since bone microenvironment represents a fertile environment that protects CSCs against the immune system, and maintains their properties and plasticity. CSCs can migrate from the primary tumor to the bone marrow (BM), due to their capacity to perform the epithelial-to-mesenchymal transition. Once in BM, they can also perform the mesenchymal-to-epithelial transition, allowing them to proliferate and initiate bone lesions. Another factor explaining the osteotropism of CSCs is their ability to recognize chemokine gradients toward BM, through the CXCL12–CXCR4 axis, also known to be involved in tumor metastasis to other organs. Moreover, the expression of CXCR4 is associated with the maintenance of CSCs’ stemness, and CXCL12 expression by osteoblasts attracts CSCs to the BM niches. CSCs localize in the pre-metastatic niches, which are anatomically distinct regions within the tumor microenvironment and govern the metastatic progression. According to the stimuli received in the niches, CSCs can remain dormant for long time or outgrow from dormancy and create bone lesions. This review resumes different aspects of the CSCs’ bone metastastic process and discusses available treatments to target CSCs. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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