Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics

Li, Yan; Tian, Bo; Yang, Jiong; Lei, Z. H.; Wu, Xin; Ye, Sheng‐Long; Liu, Yinkun; Tang, Zhao–You

doi:10.1007/s00432-004-0564-9

Cited by 188 publications

(186 citation statements)

References 27 publications

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“…It is worth noting that liver invasion was found in all metastatic tumor models. Since clinical NB metastasis occurs mostly in bone marrow and liver, our results coincide with tissue-specific metastasis of NB (Li et al, 2004). According to the results of our microarray study, RECK, VEGF, CXCL12 and CXCR4 were upregulated in metastatic NB (Azar et al, 2012;Rahmah et al, 2012).…”

Section: Discussionsupporting

confidence: 74%

Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma

Gao¹,

Chen²,

Dong³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to establish a metastatic human neuroblastoma (NB) mouse model by xenograft in order to study the metastatic mechanisms of NB. A human NB cell line was obtained from a 5-year-old patient and cultured in vitro. A suspension of these cells was subcutaneously inoculated into nude mice at the right flank next to the forelimb. The biological characteristics of the developed subcutaneous and metastatic tumors were analyzed by hematoxylin and eosin staining. The expression of the tumor marker neuron-specific enolase was determined by immunohistochemistry, and the invasive ability of metastatic tumors 16297-16307 (2015) was examined by a Matrigel invasion assay. DNA microarray analyses were performed to examine the metastasis-related gene expression. Our results showed that tumors grew in 75% of the mice injected with NB cells and the rate of metastasis was 21%. The xenograft tumors retained the morphological and biological characteristics of the NB specimen from the pediatric patient. Neuron-specific enolase was highly expressed in both subcutaneous and metastatic tumors. The metastatic tumor cells possessed a higher invasive capability than the primary NB cells. The expression of 25 metastasis-related genes was found to be significantly altered in metastatic tumors compared to primary tumors, including RECK, MMP2, VEGF, MMP3, and CXCL12. In conclusion, we successfully established a human NB xenograft model with high tumor-bearing and metastatic rates in nude mice, providing an ideal animal model for the in vivo study of NB.

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Section: Discussionsupporting

confidence: 74%

Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma

Gao¹,

Chen²,

Dong³

et al. 2015

Genet. Mol. Res.

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“…As we previously described, 22 cell lines were routinely checked for contamination by mycoplasma using Hoechst staining and were authenticated by DNA-fingerprinting and isoenzyme analyses. HCCLM3 (LM3), MHCC97-H (97H), and MHCC97-L (97L) were established in our institute 23 and authenticated by STR validation analysis during the study period. 293T cells (American Type Culture Collection, Manassas, VA) were also used in this study.…”

Section: Methodsmentioning

confidence: 99%

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

et al. 2015

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Hepatocellular carcinoma (HCC) is the third-most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis-inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down-regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5-aza-2 0 -deoxycytidine, recovers PTPRS expression in a dose-dependent manner. Conclusions: Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC. (HEPATOLOGY 2015;62:1201-1214 H epatocellular carcinoma (HCC), epidemic to Asia and Africa with an increasing incidence in Western countries, is the third-leading cause of cancer-related deaths worldwide.1 Less than 30% of HCCs are diagnosed at an early stage and are amenable for resection, liver transplantation, or local ablation.2 In advanced cases, the only effective systemic therapy is the multikinase inhibitor, sorafenib, with a partial response of only 2.2% and median overall survival (OS) of 9.2 months.3 Apart from sorafenib, several novel targeted agents or regimens have been tested; however, none of them showed any positive results, mandating alternative effective treatments.4 Therefore, understanding of the driving events of HCC progression and metastasis is of

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“…They have an identical genetic background and stepwise increasing metastatic potentials (Li et al, 2004). As shown in Figure 3a (real time PCR), the expression of HTPAP gene was downregulated in the highly metastatic potential cell line (MHCC97-H, and HCCLM3) compare with low metastatic potential HCC cell line(MHCC97-L).…”

Section: Downregulated Expression Of Htpap In Metastatic Hcc Tissues mentioning

confidence: 93%

“…They have an identical genetic background and stepwise increasing metastatic potentials (Li et al, 2004). Cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) (Gibco BRL, NY, USA) supplemented with 10% (v/v) fetal calf serum (Hyclone, Utah, USA) at 371C in a humidified incubator that contained 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

Wang

et al. 2005

Oncogene

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Our previous studies suggested that chromosome 8p deletion is associated with metastasis of hepatocellular carcinoma (HCC), in which some novel metastasis suppressor genes might be harbored. The present study aimed to identify the metastatic suppressor gene(s). A cDNA chip was constructed with the expressed sequence tags (ESTs) from chromosome 8p and used to compare the difference of expression profiling between the MHCC97-H and MHCC97-L cell lines with different metastatic potentials and similar genetic backgrounds. In all, 10 ESTs were significantly downregulated in MHCC97-H cell line with higher metastatic potential. One full-length gene, HTPAP (phosphatidic acid phosphatase type 2 domain containing 1B), was identified at chromosome 8p12. Sequencing and bioinformatic analyses revealed that HTPAP has 826 bp and encodes a putative protein of 175 amino acids with a transmembrane segment at the NH2 terminus, two protein kinase C phosphorylation site and one tyrosine kinase phosphorylation site. Its expression level in metastatic tumor tissues was much lower than that of primary HCC tissues. Both in vitro and in vivo assays suggested that HTPAP could suppress the invasion and metastasis of HCC. These suggested that HTPAP is a novel metastatic suppressor gene for HCC. The mechanism of the effect of HTPAP on HCC metastasis is not clear yet and deserves further investigation.

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Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics

Abstract: The study supports the theory that cancer metastasis is a highly selective dynamic process and the cell model system could be a useful platform for the study of HCC metastasis.

Cited by 188 publications

References 27 publications

Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma

Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

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