Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

Sethakorn, Nan; Héninger, Erika; Sánchez-de-Diego, Cristina; Ding, Adeline B.; Yada, Ravi Chandra; Kerr, Sheena C.; Kosoff, David; Beebe, David J.; Lang, Joshua M.

doi:10.3390/cancers14030757

Cited by 17 publications

(14 citation statements)

References 304 publications

(253 reference statements)

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“…AIL downregulated the expression of the osteoclast formation-associated genes and protein markers in MDA-MB-231 cells Some overexpressed genes and proteins in BC cells are associated with the invasiveness of bone metastasis and the increase of osteoclast activity, including TGF-β, CDH11, RUNX2, CXCR4, PTHrP, and MMP9 (Sethakorn et al, 2022). Therefore, it was determined how AIL affected the protein and gene expression levels in the MDA-MB-231 cells, which could help to explain the bone metastasis capacity of the BC cells.…”

Section: Ail Inhibits the In Vitro Migration Infiltration And Colony ...mentioning

confidence: 99%

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Wang

Zhong

et al. 2023

Front. Pharmacol.

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Introduction: Bone metastasis of breast cancer (BC) is a process in which the disruption of the bone homeostatic microenvironment leads to an increase in osteoclast differentiation. Ailanthus altissima shows an inhibitory effect on osteoclast differentiation. Ailanthone (AIL) refers to a natural compound isolated from Ailanthus altissima, a Chinese herbal medicine, and has effective anti-tumor activity in numerous cell lines. Its impact on bone metastases for BC is yet unclear.Methods: We measured the effect of AIL on MDA-MB-231 cells by wound healing experiments, Transwell and colony formation experiment. Using the Tartrate-resistant Acid Phosphatase (TRAP) staining tests, filamentous (F-actin) staining and bone resorption test to detect the effect of AIL on the osteoclast cell differentiation of the Bone Marrow-derived Macrophages (BMMs), activated by the MDA-MB-231 cell Conditioned Medium (MDA-MB-231 CM) and the Receptor Activator of Nuclear factor-κB Ligand (RANKL),and to explore its possibility Mechanisms. In vivo experiments verified the effect of AIL on bone destruction in breast cancer bone metastasis model mice.Results:In vitro, AIL significantly decrease the proliferation, migration and infiltration abilities of MDA-MB-231 cells at a safe concentration, and also reduced the expression of genes and proteins involved in osteoclast formation in MDA-MB-231 cells. Osteoclast cell differentiation of the BMMs, activated by MDA-MB-231 CM and RANKL, were suppressed by AIL in the concentration-dependent manner. Additionally, it inhibits osteoclast-specific gene and protein expression. It was noted that AIL inhibited the expression of the osteoclast differentiation-related cytokines RANKL and interleukin-1β (IL-1β) that were secreted by the MDA-MB-231 cells after upregulating the Forkhead box protein 3 (FOXP3) expression. Furthermore, AIL also inhibits the expression of the Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Nuclear factor-κB Ligand (NF-κB) signaling pathways, which then suppresses the MDA-MB-231CM-induced development of Osteoclasts.Conclusion: Our study shows that AIL blocks osteoclast differentiation in the bone metastasis microenvironment by inhibiting cytokines secreted by BC cells, which may be a potential agent for the treatment of BC and its secondary bone metastasis.

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Section: Ail Inhibits the In Vitro Migration Infiltration And Colony ...mentioning

confidence: 99%

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Wang

Zhong

et al. 2023

Front. Pharmacol.

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“…Glycoprotein Dikkopf-1 (DKK-1), an endogenous WNT pathway antagonist, enhances osteoclastic activity through inhibition of osteoblastic differentiation and increasing levels of RANKL [ 232 ]. Studies showed that DKK-1 was overexpressed in prostate and breast cancers and in multiple myeloma bone lesions [ 233 ].…”

Section: Emerging Targeted Therapiesmentioning

confidence: 99%

Biological and Clinical Aspects of Metastatic Spinal Tumors

Litak

Czyżewski

Szymoniuk

et al. 2022

Cancers

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Spine metastases are a common life-threatening complication of advanced-stage malignancies and often result in poor prognosis. Symptomatic spine metastases develop in the course of about 10% of malignant neoplasms. Therefore, it is essential for contemporary medicine to understand metastatic processes in order to find appropriate, targeted therapeutic options. Thanks to continuous research, there appears more and more detailed knowledge about cancer and metastasis, but these transformations are extremely complicated, e.g., due to the complexity of reactions, the variety of places where they occur, or the participation of both tumor cells and host cells in these transitions. The right target points in tumor metastasis mechanisms are still being researched; that will help us in the proper diagnosis as well as in finding the right treatment. In this literature review, we described the current knowledge about the molecular pathways and biomarkers engaged in metastatic processes involving the spine. We also presented a current bone-targeted treatment for spine metastases and the emerging therapies targeting the discussed molecular mechanisms.

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“…Solid tumors such as breast, prostate, and lung cancers frequently spread to bone, causing severe pain, disability and cancer-related deaths [ 33 ]. Tumor growth factor ß (TGF-ß), bone morphogenic protein (BMP) and Wint (Wnt) signaling pathways are key mediators of paracrine signaling between bone stromal cells and tumor cells.…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

Schirrmacher¹,

Gool²,

Stuecker³

2022

IJMS

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An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

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Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

Cited by 17 publications

References 304 publications

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Biological and Clinical Aspects of Metastatic Spinal Tumors

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

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