An Orthotopic Model of Human Osteosarcoma Growth and Spontaneous Pulmonary Metastasis

Luu, Hue H.; Kang, Qi; Park, Jong Kyung; Si, Weike; Luo, Qing; Jiang, Wei; Yin, Hong; Montag, Anthony; Simon, Michael A.; Peabody, Terrance D.; Haydon, Rex C.; Rinker‐Schaeffer, Carrie W.; He, Tong‐Chuan

doi:10.1007/s10585-005-0365-9

Cited by 208 publications

(247 citation statements)

References 51 publications

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“…To assure that this finding is not specific to only the MG63-derived sublines, we examined IGFBP5 expression in two other commonly used OS cell lines (143B and MNNG/HOS) that are not related to the MG63 lines (Figure 2b). We have previously shown that the 143B line is significantly more metastatic compared with the MNNG/HOS line (Luu et al, 2005a;Su et al, 2009). IGFBP5 mRNA and protein expression was detectable among the lines, with MNNG/HOS demonstrating the higher expression compared with the highly metastatic 143B line.…”

Section: Resultsmentioning

confidence: 86%

“…We next sought to investigate IGFBP5's role on primary tumor growth in our orthotopic animal model, using the MG63.2 and 143B cell lines that we have previously characterized (Luu et al, 2005a;Su et al, 2009). Cells were equally infected with adenovirus expressing RFP only (AdRFP), AdR-IGFBP5 or AdR-siIGFBP before subperiosteal implantation.…”

Section: Igfbp5 Inhibits Primary Tumor Growthmentioning

confidence: 99%

“…We next examined the role of IGFBP5 on spontaneous pulmonary metastases in an orthotopic xenograft model of OS using the MG63.2 and 143B cell lines that we have previously characterized (Luu et al, 2005a;Su et al, 2009). Again the cells were stably tagged with luciferase for weekly Xenogen bioluminescent imaging.…”

Section: Igfbp5 Inhibits Spontaneous Pulmonary Metastasismentioning

confidence: 99%

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Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

et al. 2011

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Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS.

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Section: Resultsmentioning

confidence: 86%

Section: Igfbp5 Inhibits Primary Tumor Growthmentioning

confidence: 99%

Section: Igfbp5 Inhibits Spontaneous Pulmonary Metastasismentioning

confidence: 99%

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Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

et al. 2011

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“…(1,2) MNNG cells are one of several recently characterized OS cell lines that mimic human OS when orthotopically xenografted into nude mice. (38) MNNG cells also express a truncated, constitutively activated version of Met, (26,27) making the MNNG cell line an appropriate model for testing the in vivo effects of PF-2341066 on OS growth. When xenografted into the proximal tibias of nude mice, MNNG cells produced rapidly growing tumors (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4) suggest that this may in fact be the case, MNNG cells have a relatively low frequency of pulmonary metastasis when injected into mouse tibias. (38) We therefore plan to test the ability of PF-2341066 to inhibit the growth of MNNG cells in lungs when xenografted via tail-vein injection. Of note, another Met inhibitor, PF-04217903, was reported recently to inhibit the pulmonary growth of OS cells xenografted using this method.…”

Section: Discussionmentioning

confidence: 99%

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Sampson

Martin

Morris

et al. 2011

Journal of Bone and Mineral Research

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Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. ß

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Establishment and Characterization of Single and Triple‐Agent Resistant Osteosarcoma Cell Lines

et al. 2022

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surgical removal and adjuvant multi-drug chemotherapy. [5,6] The combination of cisplatin (CIS), doxorubicin (DOX), and highdose methotrexate (MTX) is the standard treatment for most patients. Surgery combined with chemotherapy has improved the survival rate for osteosarcoma patients to 60-70%. [7] However, most patients with metastatic or recurrent osteosarcoma have poor prognosis due to the development of chemotherapeutic drug resistance. [8,9] One of the methods to improve the survival rate of osteosarcoma patients is by overcoming chemotherapy resistance. [10] The development of drug resistance in osteosarcoma has been studied and several mechanisms demonstrated, including genetic alterations, [11] drug-target mutation and amplification, [12] altered drug accumulation, [13] and autophagy. [14] The expression of the gene MDR1, which is responsible for producing P-glycoprotein (P-gp), has been widely studied in osteosarcoma. [15,16] P-gp is a membrane-bound protein which transports doxorubicin and methotrexate out from the cells, leading to chemoresistance. [17,18] Developing drug-resistant cancer cell models is a useful approach to study the mechanisms of chemoresistance in cancer cells. Previous resistant models have been established by using osteosarcoma cell lines such as SOSP-9607, [19] Saos-2, [20] MG-63, [21] and U-2OS. [22] These established osteosarcoma resistant models have increased fold resistance ranges from 6 to 120-fold compared to their parental cell lines. [19][20][21][22] They also exhibit cross-resistance to other chemotherapeutic drugs including ifosfamide, epidoxorubicin, pirarubicin, and paclitaxel. [19][20][21][22] In the present study, clinically relevant chemo-resistant osteosarcoma cell models were developed from the cell lines MG-63 and HOS-143B. MG-63 was established from a 14-year old male with marginally metastatic osteosarcoma; [23] and HOS-143B originally derived from HOS, was established from a 13-year old Caucasian female with significant metastatic characteristics. [24] Chemo-resistant models of MG-63 and HOS-143B were developed by using a pulsed-selection strategy where cells were incubated with constant concentration of chemotherapeutic drugs for 72 h and then allowed to recover in drug-free media. The purpose of this method is to simulate a similar experience with osteosarcoma patients who undertake clinical chemotherapy treatment; and therefore, this is a clinically Two human osteosarcoma cell lines (MG-63 and HOS-143B) are developed into drug-resistant models using a short-term drug exposure and recovery in drug-free media. Cisplatin, doxorubicin, and methotrexate are used as single agents and in triple combination. The highest level of resistance to cisplatin is observed in MG-63/CISR8, doxorubicin in HOS-143B/DOXR8, and methotrexate in HOS-143B/MTXR8. The MG-63/TRIR8 and HOS-143B/TRIR8 tripleresistance models show lower levels of resistance to combination treatment and are not resistant to the drugs individually. Apoptosis assays suggest that the resistance in MG-63/TRI...

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An Orthotopic Model of Human Osteosarcoma Growth and Spontaneous Pulmonary Metastasis

Cited by 208 publications

References 51 publications

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Establishment and Characterization of Single and Triple‐Agent Resistant Osteosarcoma Cell Lines

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