Notch signaling contributes to the pathogenesis of human osteosarcomas

Engin, Feyza; Bertin, Terry; Ma, Ou; Jiang, Ming; Wang, Lisa; Sutton, Richard E.; Donehower, Lawrence A.; Lee, Brendan

doi:10.1093/hmg/ddp057

Cited by 154 publications

(148 citation statements)

References 24 publications

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“…Studies thus far on the Notch pathway in osteosarcoma are rather limited. (31,32) Metastases A defining feature of osteosarcoma is the high rate of metastasis that results from the primary bone tumor disseminating to distant secondary sites by a hematogenous route. Despite the use of multimodality and multiagent systemic cancer therapy before and after management of the primary tumor, the vast majority of deaths seen in osteosarcoma patients occur as a result of metastases.…”

Section: Etiology Of Osteosarcomamentioning

confidence: 99%

Osteosarcoma

Görlick

Khanna

2010

Journal of Bone and Mineral Research

154

126

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It has been difficult to identify the molecular features central to the pathogenesis of osteosarcoma owing to a lack of understanding of the cell or origin, the absence of identifiable precursor lesions, and its marked genetic complexity at the time of presentation. Interestingly, several human genetic disorders and familial cancer syndromes, such as Li-Fraumeni syndrome, are linked to an increased risk of osteosarcoma. Association of these same genetic alterations and osteosarcoma risk have been confirmed in murine models. Osteosarcoma is associated with a variety of genetic abnormalities that are among the most commonly observed in human cancer; it remains unclear, however, what events initiate and are necessary to form osteosarcoma. The availability of new resources for studying osteosarcoma and newer research methodologies offer an opportunity and promise to answer these currently unanswered questions. Even in the absence of a more fundamental understanding of osteosarcoma, association studies and preclinical drug testing may yield clinically relevant information. ß

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Section: Etiology Of Osteosarcomamentioning

confidence: 99%

Osteosarcoma

Görlick

Khanna

2010

Journal of Bone and Mineral Research

154

126

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“…(38) However, several reports have shown that osteoblast cells expressed Notch1, and BMP-2 did not have an appreciable effect on Notch1 expression. (39)(40)(41) Moreover, osteoblast differentiation can occur despite Notch1 expression. For this reason, it was expected that Notch1 signaling could be modulated during osteoblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Ann

Kim

Choi

et al. 2010

Journal of Bone and Mineral Research

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Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR‐IB/Alk6‐induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1‐IC‐RBP‐Jk complex. Using deletion mutants, we also determined that the N‐terminal domain of Runx2 was crucial to the binding and inhibition of the N‐terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation. © 2011 American Society for Bone and Mineral Research.

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“…Some recent studies have demonstrated the transcriptional activation of MMP9 and uPA by Notch1 in human prostate cancer 19 and the participation of Notch1 signaling in pancreatic cancer 20 and osteosarcoma. 21 In breast cancer, the suppression of E-cadherin expression occurs through the Jagged1-Notch1-Slug EMT pathway. 22 In human HCC, EMT and tumor metastasis are not well defined, although Twist, a down-stream transcription factor of the EMT pathways, has been found to be positively correlated with metastasis and down-regulation of E-cadherin.…”

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confidence: 99%

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the reestablishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and is ranked second amongst all cancer deaths in Hong Kong. HCC is correlated with an increased likelihood of vascular invasion, metastasis and recurrence (even after surgical resection), leading to poor prognosis. 1 Metastasis, both intrahepatic and extrahepatic, is of particular concern and occurs in more than half of HCC cases. 2 The incidence of high grade HCC that metastasize to distant sites is high. 2 However, the detailed mechanisms of metastasis are yet to be revealed.The process that converts adherent epithelial cells into migratory cells to invade the extracellular matrix is called the epithelial-mesenchymal transition (EMT). This process plays fundamental roles in tissue and organ formation during embryonic development and in wound healing and tissue repair during adult life. 3,4 However, the abnormal activation of EMT programs can be disadvantageous to cancer patients. 3 EMT can allow carcinoma cells to acquire mesenchymal cell gene expression profiles and properties, 5 leading to the transformation of the cells from being coherent and displaying apicobasal polarity to become nonpolarized cells that can move through the extracellular media. This transformation enables the spread of tumor cells to distant sites. 6,7 Although EMT is considered to be the first step in the metastatic progression of migratory cancer cells, EMT has not been confirmed to exist in vivo. 3...

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Notch signaling contributes to the pathogenesis of human osteosarcomas

Cited by 154 publications

References 24 publications

Osteosarcoma

Osteosarcoma

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

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