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Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies
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Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 20024

Special Issue Editor

Prof. Dr. Ingunn Holen

E-Mail Website
Guest Editor
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Interests: breast cancer; bone metastases; microenvironment; bone microvasculature; tumour cell dormancy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bone metastases, a common feature of advanced breast and prostate cancer, are increasingly also found in patients with other cancers (e.g., lung, renal) due to improved treatment of the primary tumor and, hence, prolonged survival. However, once skeletal involvement is established, patient survival is limited and treatment often restricted to palliation. The main therapies offered are bone-targeted anti-resorptive agents, used to prevent and/or reduce disabling skeletal related events like pain, fractures and spinal cord compression. However, no current treatment specifically prevents the development of bone metastases.

Development of novel therapeutic approaches to improve outcome for these poor-prognosis patients requires a better understanding of the molecular and cellular mechanisms that underpin tumor cell dissemination, homing, survival, colonization, and progression in bone. In particular, the complex multifactorial role of the microenvironment in regulation of cancer cell dormancy in bone niches, as well as identification of the signals that trigger escape from dormancy, remains to be elucidated. Another main area of interest is how tumor cell interactions with the bone microenvironment may represent therapeutic targets, in particular in relation to new treatment modalities like immunotherapy. The importance of both the innate and the adaptive immune response to the presence of tumor cells in bone also needs to be clarified.

This Special Issue is the second in the series and will contain a collection of manuscripts describing investigations into the different stages of bone metastasis, covering a range of model systems and tumor types, reflecting our current knowledge and highlighting recent progress in this rapidly changing field.

Prof. Dr. Ingunn Holen
Guest Editor

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

  • Bone
  • Bone microenvironment
  • Bone niches
  • Bone metastases
  • Disseminated tumor cells
  • Extracellular matrix
  • Solid tumors
  • Tumor cell dormancy
  • Osteoimmunology
  • Immunotherapy

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Published Papers (5 papers)

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Research

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14 pages, 9790 KiB  
Article
CD73/Adenosine Pathway Involvement in the Interaction of Non-Small Cell Lung Cancer Stem Cells and Bone Cells in the Pre-Metastatic Niche
by Giulia Bertolini, Mara Compagno, Dimas Carolina Belisario, Cristiano Bracci, Tullio Genova, Federico Mussano, Massimo Vitale, Alberto Horenstein, Fabio Malavasi, Riccardo Ferracini and Ilaria Roato
Int. J. Mol. Sci. 2022, 23(9), 5126; https://doi.org/10.3390/ijms23095126 - 4 May 2022
Cited by 11 | Viewed by 2672
Abstract
Adenosinergic signaling is an important regulator of tissue homeostasis and extracellular accumulation of adenosine (Ado) and is associated with different pathologies, such as cancer. In non-small-cell lung cancer (NSCLC), a subset of CD133/CXCR4+ cancer stem cell (CSCs) has been demonstrated to initiate bone [...] Read more.
Adenosinergic signaling is an important regulator of tissue homeostasis and extracellular accumulation of adenosine (Ado) and is associated with different pathologies, such as cancer. In non-small-cell lung cancer (NSCLC), a subset of CD133/CXCR4+ cancer stem cell (CSCs) has been demonstrated to initiate bone metastases. Here we investigated how NSCLC CSCs interact with osteoclasts (OCs) and osteoblasts (OBs) by modulating Ado production and OC activity. We proved that CSC-spheres, generated in vitro from NSCLC cell lines, express CD38, PC-1, and CD73, enzymes of the non-canonical adenosinergic pathway, produce high level of Ado, and down-regulate A1R and A3R inhibitory receptors, while expressing A2AR and A2BR. To address the Ado role and modulation of the in-bone pre-metastatic niche, we performed co-cultures of CSC-spheres with OCs and OBs cells. Firstly, we verified that active OCs do not activate non-canonical the adenosinergic pathway, conversely to OBs. OCs co-cultured with CSC-spheres increase Ado production that is related to the OC resorption activity and contributes to T-cell suppression. Finally, we proved the efficacy of anti-CD73 agents in blocking NSCLC cell migration. Overall, we assessed the importance of adenosinergic signaling in the interaction between CSCs and OCs at the pre-metastatic niche, with therapeutic implications related to Ado production. Full article
(This article belongs to the Special Issue Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies)
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21 pages, 3575 KiB  
Article
A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression
by Julia N. Cheng, Jennifer B. Frye, Susan A. Whitman, Andrew G. Kunihiro, Ritu Pandey and Janet L. Funk
Int. J. Mol. Sci. 2021, 22(9), 4463; https://doi.org/10.3390/ijms22094463 - 24 Apr 2021
Cited by 7 | Viewed by 2728
Abstract
While tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine [...] Read more.
While tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGFβ signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E2)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGFβ receptors II and I, only cells with TGFβ-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in >90% of clinical BMETs, also tracked with osteolytic potential; TGFβ and E2 each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGFβ neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFβ may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGFβ signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic. Full article
(This article belongs to the Special Issue Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies)
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Review

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14 pages, 5329 KiB  
Review
Osteosarcoma and Metastasis Associated Bone Degradation—A Tale of Osteoclast and Malignant Cell Cooperativity
by Kirstine Sandal Nørregaard, Henrik Jessen Jürgensen, Henrik Gårdsvoll, Lars Henning Engelholm, Niels Behrendt and Kent Søe
Int. J. Mol. Sci. 2021, 22(13), 6865; https://doi.org/10.3390/ijms22136865 - 25 Jun 2021
Cited by 32 | Viewed by 3955
Abstract
Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, [...] Read more.
Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process. Full article
(This article belongs to the Special Issue Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies)
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23 pages, 5575 KiB  
Review
The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone
by Andy Göbel, Stefania Dell’Endice, Nikolai Jaschke, Sophie Pählig, Amna Shahid, Lorenz C. Hofbauer and Tilman D. Rachner
Int. J. Mol. Sci. 2021, 22(10), 5078; https://doi.org/10.3390/ijms22105078 - 11 May 2021
Cited by 22 | Viewed by 4742
Abstract
Tumor metastasis to bone is a common event in multiple forms of malignancy. Inflammation holds essential functions in homeostasis as a defense mechanism against infections and is a strategy to repair injured tissue and to adapt to stress conditions. However, exaggerated and/or persistent [...] Read more.
Tumor metastasis to bone is a common event in multiple forms of malignancy. Inflammation holds essential functions in homeostasis as a defense mechanism against infections and is a strategy to repair injured tissue and to adapt to stress conditions. However, exaggerated and/or persistent (chronic) inflammation may eventually become maladaptive and evoke diseases such as autoimmunity, diabetes, inflammatory tissue damage, fibrosis, and cancer. In fact, inflammation is now considered a hallmark of malignancy with prognostic relevance. Emerging studies have revealed a central involvement of inflammation in several steps of the metastatic cascade of bone-homing tumor cells through supporting their survival, migration, invasion, and growth. The mechanisms by which inflammation favors these steps involve activation of epithelial-to-mesenchymal transition (EMT), chemokine-mediated homing of tumor cells, local activation of osteoclastogenesis, and a positive feedback amplification of the protumorigenic inflammation loop between tumor and resident cells. In this review, we summarize established and evolving concepts of inflammation-driven tumorigenesis, with a special focus on bone metastasis. Full article
(This article belongs to the Special Issue Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies)
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17 pages, 1042 KiB  
Review
Interleukins as Mediators of the Tumor Cell—Bone Cell Crosstalk during the Initiation of Breast Cancer Bone Metastasis
by Marie-Therese Haider, Nicole Ridlmaier, Daniel J. Smit and Hanna Taipaleenmäki
Int. J. Mol. Sci. 2021, 22(6), 2898; https://doi.org/10.3390/ijms22062898 - 12 Mar 2021
Cited by 19 | Viewed by 5078
Abstract
Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for [...] Read more.
Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for these patients. Bone is among the most frequent sites of metastasis in breast cancer. Once in the bone, disseminated tumor cells can acquire a dormant state and remain quiescent until they resume growth, resulting in overt metastasis. At this stage the disease is characterized by excessive, osteoclast-mediated osteolysis. Cells of the bone microenvironment including osteoclasts, osteoblasts and endothelial cells contribute to the initiation and progression of breast cancer bone metastasis. Direct cell-to-cell contact as well as soluble factors regulate the crosstalk between disseminated breast cancer cells and bone cells. In this complex signaling network interleukins (ILs) have been identified as key regulators since both, cancer cells and bone cells secrete ILs and express corresponding receptors. ILs regulate differentiation and function of bone cells, with several ILs being reported to act pro-osteoclastogenic. Consistently, the expression level of ILs (e.g., in serum) has been associated with poor prognosis in breast cancer. In this review we discuss the role of the most extensively investigated ILs during the establishment of breast cancer bone metastasis and highlight their potential as therapeutic targets in preventing metastatic outgrowth in bone. Full article
(This article belongs to the Special Issue Tumour Cell Dissemination in Bone: Pathophysiology and Therapeutic Strategies)
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