Bone metastasis: the importance of the neighbourhood

Croucher, Peter I.; McDonald, Michelle M.; Martın, Thomas

doi:10.1038/nrc.2016.44

Cited by 382 publications

(369 citation statements)

References 215 publications

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“…This hypothesis was confirmed, and became the so-called “circulation theory” [22]. Current studies indicate that the development of bone metastases is a multi-step process [23, 24]. After the tumor has progressed to locally invade the vessels, few disseminated tumor cells are released and evade the immune system, circulating from the primary tumor site to the bone.…”

Section: Pathogenesis Of Bone Metastasesmentioning

confidence: 68%

Molecular Regulation of Bone Metastasis Pathogenesis

Yiang

et al. 2018

Cell Physiol Biochem

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Distant metastases are the major cause of mortality in cancer patients. Bone metastases may cause bone fractures, local pain, hypercalcemia, bone marrow aplasia, and spinal cord compression. Therefore, the management of bone metastases is important in cancer treatment. Normal bone remodeling is regulated by osteoprotegerin ligand (OPGL), receptor activator of NF-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and other cytokines. In the tumor microenvironment, tumor cells induce a vicious cycle that promotes osteoblastic and osteolytic lesions. Studies support the idea that distant metastases may occur due to the immunosuppressive function of myeloid-derived suppressor cells (MDSCs). These cells inhibit T cells and natural killer (NK) cells and differentiate into tumor-associating macrophages (TAMs), monocytes, and dendritic cells (DCs). In this review, we summarize studies focusing on the role of MDSCs in bone metastasis and provide a strong foundation for developing anticancer immune treatments and anticancer therapies, in general.

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Section: Pathogenesis Of Bone Metastasesmentioning

confidence: 68%

Molecular Regulation of Bone Metastasis Pathogenesis

Yiang

et al. 2018

Cell Physiol Biochem

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“…There are likely to be many factors that enable meta-static tumor cells to become quiescent in the bone or any other distant site, but few have been identified [23]. In fact we know practically nothing about how tumor cells enter a dormant state.…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

Hallmarks of Bone Metastasis

Johnson

Suva

2017

Calcif Tissue Int

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Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient’s quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

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“…Current treatments – radiation, surgery, chemotherapy, and antiresorptive drugs – can improve quality of life but are rarely curative, with limited effect on overall survival (3-5). Treating breast cancer bone metastases has proven difficult due to frequent dissemination of metastases throughout the skeleton, a lack of tumor-specific targets expressed across breast cancer subtypes, and the chemo-protective nature of the bone microenvironment (2,6,7). …”

Section: Introductionmentioning

confidence: 99%

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

et al. 2017

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Bone metastases occur in ~70% of metastatic breast cancer patients often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3) which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n=42). Mechanistic investigations revealed that TGF-β signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ~12.5nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared to equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared to free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site.

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Bone metastasis: the importance of the neighbourhood

Cited by 382 publications

References 215 publications

Molecular Regulation of Bone Metastasis Pathogenesis

Molecular Regulation of Bone Metastasis Pathogenesis

Hallmarks of Bone Metastasis

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

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