Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis

Zhang, Pingyu; Yang, Yanwen; Zweidler‐McKay, Patrick A.; Hughes, Dennis P.M.

doi:10.1158/1078-0432.ccr-07-1992

Cited by 136 publications

(141 citation statements)

References 41 publications

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“…34 Previous observations of Notch signaling mediating tumor invasion and metastasis have been limited to only cancer cell lines. 19,36 Our results demonstrate that clinically, abnormal Notch1 expression strongly correlates with tumor metastatic disease in HCC patients, and our study provides the first evidence that Notch signaling might promote tumor metastasis in human cancer from the clinical disease point of view. The Notch signaling pathway includes Notch receptors, ligands, modifiers and Notch targeting transcription factors.…”

Section: Discussionsupporting

confidence: 53%

“…Using over-expression and knock-down of Notch signaling by siRNA or inhibitors, activated Notch1 signaling has been reported to be involved in tumor development, 32 tumor growth, 33 tumor angiogenesis, 34 chemotherapy sensitivity 35 and invasion of tumor cells by limiting the migration of tumor cells. 17,19,20,36 For the first time, our study demonstrated that knocking-down Notch1 was able to inhibit liver tumor metastasis in vivo in a mouse model. Therefore, targeting the Notch pathway could be a potential treatment for tumor metastasis.…”

Section: Targeting Notch1 Decreases Metastatic Hcc Cell Motility In Vmentioning

confidence: 75%

“…Moreover, alterations of Notch signaling that function in tumor initiation, progression, angiogenesis and metastasis have been found to be mediated through the activation of several important downstream pathways. Until now, b-catenin, 17 AKT, 32,33,38 Pin1, 39 Snail, 22 MMP9 19 and HES1 36 have been reported to either function as the downstream targets or be associated with Notch signaling in cancers. Notch signaling induces EMT Figure 4.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 53%

Section: Targeting Notch1 Decreases Metastatic Hcc Cell Motility In Vmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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“…[34][35][36][37] Hes1 loss of function via a dominant-negative mastermind (dnMAM) in an osteosarcoma xenograft model, which then results in a significant reduction of lung metastasis neoplasm, while dnMAM has no effect on tumor latency or tumor growth rates. 38 Evidence from 56 samples obtained from patients who did well with osteosarcoma and died from metastasis reveals that Hes1 is inversely correlated with survival. 37 The metastasis potentiality of Hes1 was further studied in vitro by constructing mutant Hes1 fragments which were then transfected into osteosarcoma cells.…”

Section: Overview Of Hes1 Factormentioning

confidence: 99%

Hes1: a key role in stemness, metastasis and multidrug resistance

Liu¹,

Dai²,

Du³

2015

Cancer Biology & Therapy

164

116

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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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Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis

Cited by 136 publications

References 41 publications

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

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

Hes1: a key role in stemness, metastasis and multidrug resistance

Osteosarcoma

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