Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma

Shimizu, Takatsune; Ishikawa, T.; Iwai, Sayaka; Ueki, Arisa; Sugihara, Eiji; Onishi, Nobuyuki; Kuninaka, Shinji; Miyamoto, Takeshi; Toyama, Yoshiaki; Ijiri, Hiroshi; Mori, Hajime; Matsuzaki, Yuji; Yaguchi, Tomonori; Nishio, Hiroshi; Kawakami, Yutaka; Ikeda, Yasuo; Saya, Hideyuki

doi:10.1158/1541-7786.mcr-11-0347

Cited by 33 publications

(48 citation statements)

References 48 publications

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“…14,22-25 FGF2 produced by tumorassociating fibroblasts reportedly contributes to maintain cellular immaturity and aggressiveness. 23 Interestingly, we found that inhibition of osteoblastic differentiation by TNFa or IL-1 through ERK was required for AX cell tumorigenesis through the maintenance of an undifferentiated state. Although IL-6 is an inflammatory cytokine implicated in tumorigenesis of various cancers, 15,16 IL-6 was not required for tumor development in this osteosarcoma model.…”

Section: Discussionmentioning

confidence: 85%

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

et al. 2013

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Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFa is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wildtype mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFa-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFa treatment, suggesting that TNFa maintains AX cells in an undifferentiated state. TNFa inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFa inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1a/IL-1b doubly deficient mice. We found that both TNFa and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFa/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

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Section: Discussionmentioning

confidence: 85%

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

et al. 2013

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“…The abundance of target mRNAs was determined relative to that of ACTB mRNA. For mouse samples, total RNA extraction, reverse transcription, and real-time PCR analysis was performed as described previously (12). Sets of primers for real-time PCR are listed in Supplementary Table S1.…”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

“…For preparation of a tumor homogenate, small fragments were suspended in the same buffer and disrupted using Biomasher (Nippi) and ultrasonic treatment. Immunoblot analysis was performed as previously described (11,12). Actin or a-tubulin was examined as a loading control.…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…Immunohistochemical analysis was performed as previously described (11,12) using antibodies to GFP (Santa Cruz Biotechnology) and LC3 (MBL). For immunofluorescent staining, cells were fixed with ice-cold acetone for 5 minutes for Ki67 and phospho-histone H2AX or 4% paraformaldehyde for 15 minutes for phospho-histone H3, respectively, washed 3 times with PBS, exposed to PBS containing 3% BSA for 1 hour, and stained with antibodies to Ki67, phosphohistone H2AX, or phospho-histone H3 (Cell Signaling Technology).…”

Section: Immunostainingmentioning

confidence: 99%

“…Injection of highly tumorigenic cells (designated AXT cells) into syngeneic mice results in the development of lethal osteosarcoma with metastatic lesions that mimics human osteoblastic osteosarcoma (11). We previously showed that cellular heterogeneity as well as therapeutic resistance in this model can be brought about by soluble factors released from the tumor microenvironment (12).…”

Section: Introductionmentioning

confidence: 99%

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IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress

et al. 2014

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Osteosarcoma is a malignant bone tumor in children and adolescents characterized by intrinsic therapeutic resistance. The IGF2 is expressed at elevated levels in osteosarcoma after treatment with chemotherapy, prompting an examination of its functional contributions to resistance. We found that continuous exposure to IGF2 or insulin in the absence of serum created a dormant growth state in osteosarcoma cells that conferred resistance to various chemotherapeutic drugs in vitro. Mechanistic investigations revealed that this dormant state correlated with downregulation of downstream signaling by the IGF1 receptor, heightened cell survival, enhanced autophagy, and the presence of extracellular glutamine. Notably, inhibiting autophagy or depleting glutamine was sufficient to increase chemotherapeutic sensitivity in osteosarcoma xenografts in mice. Clinically, we confirmed that IGF expression levels were elevated in human osteosarcoma specimens from patients who received chemotherapy. Together, our results suggest that activation of IGF or insulin signaling preserves the survival of osteosarcoma cells under chemotherapeutic stress, providing a drug-resistant population that may engender minimal residual disease. Attenuating this survival mechanism may help overcome therapeutic resistance in osteosarcoma. Cancer Res; 74(22); 6531-41. Ó2014 AACR.

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MEK inhibition preferentially suppresses anchorage‐independent growth in osteosarcoma cells and decreases tumors in vivo

Shimizu

Kimura

Sugihara

et al. 2021

Journal Orthopaedic Research

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Osteosarcoma is the most common high‐grade malignancy of bone, and novel therapeutic options are urgently required. Previously, we developed mouse osteosarcoma AXT cells that can proliferate both under adherent and nonadherent conditions. Based on metabolite levels, nonadherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified MEK inhibitors, including trametinib, that preferentially decreased the viability of nonadherent AXT cells. Trametinib inhibited the cell cycle and induced apoptosis in AXT cells, and both effects were stronger under nonadherent conditions. Trametinib also potently decreased viability in U2OS cells, but its effects were less prominent in MG63 or Saos2 cells. By contrast, MG63 and Saos2 cells were more sensitive to PI3K inhibition than AXT or U2OS cells. Notably, the combination of MAPK/ERK kinase (MEK) and PI3K inhibition synergistically decreased viability in U2OS and AXT cells, but this effect was less pronounced in MG63 or Saos2 cells. Therefore, signal dependence for cell survival and crosstalk between MEK–ERK and PI3K–AKT pathways in osteosarcoma are cell context‐dependent. The activation status of other kinases including CREB varied in a cell context‐dependent manner, which might determine the response to MEK inhibition. A single dose of trametinib was sufficient to decrease the size of the primary tumor and circulating tumor cells in vivo. Moreover, combined administration of trametinib and rapamycin or conventional anticancer drugs further increased antitumor activity. Thus, given optimal biomarkers for predicting its effects, trametinib holds therapeutic potential for the treatment of osteosarcoma.

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Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma

Cited by 33 publications

References 48 publications

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress

MEK inhibition preferentially suppresses anchorage‐independent growth in osteosarcoma cells and decreases tumors in vivo

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