Osteoclasts in Osteosarcoma: Mechanisms, Interactions, and Therapeutic Prospects

Figures & data

Figure 1 Osteoclasts in the osteosarcoma microenvironment. Osteosarcoma cells and osteoblasts in the tumor microenvironment affect osteoclasts through direct and indirect ways, leading to changes in osteoclasts. Osteoclasts produce related factors, which in turn regulate osteosarcoma cells and osteoblasts, and then activated or stimulated osteosarcoma cells and osteoblasts affect osteoclasts in a direct or indirect way, forming a vicious cycle. Osteosarcoma cells and tumor-associated fibroblasts melt in the osteosarcoma microenvironment and undergo multi-nucleated osteoclast-like changes. The myeloid-derived suppressor cells produce high levels of HIF-1 in hypoxia environment, thus producing NO-mediated osteoclast differentiation, and NO can also mediate HIF-1 increase through PI3K and AKT pathways, thus forming a positive feedback.

Figure 2 Osteoclasts in the bone marrow microenvironment. In the bone marrow microenvironment, stimulated by RANKL and M-CSF, TLR2 binds to SIGLEC-15, resulting in the fusion of mononuclear macrophages into polykaryotes and the final differentiation into osteoclasts. T cell expression of TNFSF11 encoding RANKL can also activate osteoclasts. In addition, DCs has been found in advanced bone metastases from breast cancer to differentiate into DC-OCs upon contact with T cells. Such osteoclasts can secrete IL-23, and binding to IL-23R on T cells also promotes the production of activated osteoclasts in RANKL.

Table 1 Interactions Between Osteoclasts and Other Cells in the Osteosarcoma Microenvironment

Type of Study	Type of Immune Cells	Type of Ligand/Receptor	Chemical Available Agonists/Antagonists	Reference
In vitro	Mononuclear	RANKL/TNFSF11	LiCl	[58]
In-vitro, in-vivo	Macrophages	Sialyl-Tn carbohydrate ligand	IFN-γ	[59]
In-vitro, in-vivo	Macrophages	Siglec-15	NP-159 (Siglec-15 neutralizing antibody)	[60]
In-vitro, in-vivo	Macrophages	Sialylated TLR2	SialEXO 23 α2,3 specific sialidase	[61]
In-vitro, in-vivo	Myeloid-derived suppressor cell, tumor-associated macrophages	CD11b cells	Metformin (Met)	[67]
In-vivo, in-situ	Myeloid-derived suppressor cell	CXCL12	AMD3100(a CXCR4 antagonist)	[68]
In vitro, in-situ	Tumor-associated fibroblasts	α-Smooth muscle actin-positive fibroblasts	Still unclear	[69]
In vitro	T cells	RANKL/TNFSF11	Anti-CD3/CD28, PMA/Ionomycin	[70]
In-vitro, in-vivo	Dendritic cells, T cells	IL-23, IL-23R, RANKL	Anti-IL23 monoclonal antibody	[71]

Table 2 Osteosarcoma Treatment Related Clinical Trials

Research ID	Research Name	Primary Research Objective	Interventions	Status	Trial Phase	Primary Completion	Enrollment
NCT00586846	Phase II Study of Chemotherapy and Pamidronate for the Treatment of Newly Diagnosed Osteosarcoma	This study is designed to test the safety and feasibility of the simultaneous administration of a biphosphonate with chemotherapy for the treatment of osteosarcoma in newly diagnosed patients.	Drug: Cisplatin Drug: Doxorubicin Drug: Methotrexate	Completed	Phase 2	2009–02	40
NCT02470091	Denosumab in Treating Patients With Recurrent or Refractory Osteosarcoma	This phase II trial studies how well denosumab works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as denosumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.	Biological: Denosumab Other: Laboratory Biomarker Analysis Other: Pharmacological Study	Active, not recruiting	Phase 2	2023-09-30	56
NCT00330421	Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)	This phase II trial is studying how well sorafenib works in treating patients with soft tissue sarcoma. Sorafenib may stop the growth of soft tissue sarcoma by blocking blood flow to the tumor and blocking some of the enzymes needed for tumor cell growth.	Drug: sorafenib tosylate Procedure: therapeutic conventional surgery Other: laboratory biomarker analysis Other: pharmacological study Procedure: computed tomography Procedure: dynamic contrast-enhanced magnetic resonance imaging	Completed	Phase 2	2008–07	15
NCT00880542	Sorafenib and Ifosfamide in Treating Patients With High-Grade Soft Tissue Sarcoma or Bone Sarcoma That Can Be Removed by Surgery	This phase II trial is studying the side effects of giving sorafenib together with ifosfamide and to see how well it works in treating patients with high-grade soft tissue sarcoma or bone sarcoma that can be removed by surgery.	Drug: sorafenib Drug: Ifosfamide	Terminated	Phase 2	2010–11	7
NCT01946529	Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors	This protocol will study treatment for Ewing sarcoma family of tumors (ESFT) and desmoplastic small round cell tumor (DSRCT). Participants with ESFT will be divided into two treatment groups, A or B, based on tumor characteristics. Group A (standard risk) participants have tumor that is not in the pelvis, has not spread to other parts of the body, and are less than 14 years of age. Because previous clinical trials have shown that standard treatment is very effective for children whose tumors have these characteristics, these participants will receive standard treatment. Group B (high risk) participants are 14 years of age or older or have tumor in the pelvis, or the tumor has spread to other parts of the body. Participants with DSRCT in the abdomen and/or pelvis or with tumor that cannot be removed by surgery alone or has spread to other parts of the body will be included in Group B. Participants in this group are considered high risk because there is a greater chance of tumor recurring following standard treatments currently in use. All participants will be followed and evaluated for 10 years following completion of therapy.	Drug: vincristine Drug: doxorubicin Drug: cyclophosphamide	Active, not recruiting	Phase 2	2026–07	24
NCT02357810	Pazopanib Hydrochloride and Topotecan Hydrochloride in Treating Patients With Metastatic Soft Tissue and Bone Sarcomas	The purpose of this clinical research study is to learn if pazopanib when given in combination with topotecan can help to control sarcomas. The safety of this drug combination will also be studied. Pazopanib hydrochloride and topotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.	Drug: Pazopanib Hydrochloride Drug: Oral Topotecan Hydrochloride Other: Laboratory Biomarker Analysis	Completed	Phase 2	2021-10-12	178
NCT02180867	Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery	This randomized phase II/III trial studies how well pazopanib, when combined with chemotherapy and radiation therapy or radiation therapy alone, work in the treatment of patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can eventually be removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether these therapies can be safely combined and if they work better when given together in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.	Drug: Doxorubicin Drug: Doxorubicin Hydrochloride Drug: Ifosfamide Drug: Pazopanib Drug: Pazopanib Hydrochloride Radiation: Radiation Therapy Procedure: Therapeutic Conventional Surgery	Active, not recruiting	Phase 2 Phase 3	2019-06-30	140
NCT01532687	Gemcitabine With or Without Pazopanib in Treating Patients With Refractory Soft Tissue Sarcoma	This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether gemcitabine hydrochloride is more effective with or without pazopanib hydrochloride in treating patients with soft tissue sarcoma.	Drug: Gemcitabine Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Drug: Pazopanib Drug: Pazopanib Hydrochloride Other: Placebo Administration	Completed	Phase 2	2019-10-31	54

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