Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways

Zhou, Tianhong; Xiao, Xiaoping; Xu, Bin; Li, Hongjian; Zou, Yi Ming

doi:10.1080/02841860802314746

Cited by 20 publications

(12 citation statements)

References 20 publications

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“…Moreover, for somatotropinomas, Taboada et al (31) have shown that patients who have high SSTr2-SSTr5 messenger RNA tumor levels respond better to octreotide therapy than those with low ratios. In vivo animal studies have also shown that SSTr2-transfected xenografts are more sensitive to somatostatin treatment (32,33), and the SSTr2-transfected tumors grow more slowly than WT tumors. For example, Vernejoul et al observed that endogenous somatostatin was able to suppress the growth after in vivo SSTr2 gene transfer to orthotopically implanted pancreatic tumors (32).…”

Section: Discussionmentioning

confidence: 99%

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC

Zhang¹,

Moroz²,

Serganova³

et al. 2010

J Nucl Med

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The human somatostatin receptor subtype 2 (hSSTr2)-68 Ga-DOTATOC reporter system has several attractive features for potential translation to human studies. These include a low expression of hSSTr2 in most organs, a rapid internalized accumulation of 68 Ga-DOTATOC in the SSTr2-expressing cells, and a rapid excretion of unbound radioligand by the renal system. We performed a series of in vitro and in vivo validation studies of this reporter system. Methods: A retroviral vector containing a dual reporter, pQCXhSSTr2-IRES-GFP (IRES: internal ribosome entry site; GFP: green fluorescent protein), was constructed and transduced into Jurkat, C6, and U87 cells. Stably transduced reporter cells were characterized in vitro using optical and radiometric methods. Multiple tumor-bearing mice were evaluated with 68 Ga-DOTATOC PET studies. Results: The dual-reporter genes were incorporated into all tumor cell lines, and their expression levels were confirmed by fluorescence-activated cell sorting (FACS), GFP visualization, and reverse-transcriptase polymerase chain reaction (RT-PCR) analysis for hSSTr2. In vitro, hSSTr2 cell membrane expression was 36,000, 280,000, and 1,250,000 copies per cell for the SSTR2-transfected Jurkat, U87, and C6 cell lines. Small-animal PET of 68 Ga-DOTATOC in tumor-bearing mice demonstrated that the in vivo uptake of this radioligand was directly proportional to the in vitro expression of hSSTr2. The in vivo uptake of 68 Ga-DOTATOC, at 2 h after injection, was low in all organs except the kidneys (7.8 percentage of injected dose per gram [%ID/g]) and as high as 15.2 %ID/g in transduced C6 tumors. The corresponding transduced-to-nontransduced tumor uptake ratio was 64, and the tumor-to-muscle uptake ratio was around 500. Conclusion: 68 Ga-DOTATOC is an excellent specific ligand for this hSSTr2 reporter system and for hSSTr2 reporter gene PET. Because DOTATOC has undergone extensive clinical testing, this human reporter system has the potential for translation to human studies.

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Section: Discussionmentioning

confidence: 99%

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC

Zhang¹,

Moroz²,

Serganova³

et al. 2010

J Nucl Med

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“…Among these 5 receptors, SSTR2 expression is found in many tumor cells, in particular in HCC. It has been reported that SSTR2 mediates the inhibitory effects of SST on tumor cell growth more efficiently than the others because of its strongest affinity for octreotide (OCT), an SST analogue [9][10][11][12][13][14][15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and Influence of Octreotide-Induced Regulation of Somatostatin Receptor 2 on Hepatocellular Carcinoma

Hua

Yin²,

Peng³

et al. 2009

Chemotherapy

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Background: Somatostatin receptors (SSTRs) belong to the family of G protein-coupled receptors. Exposure of G protein-coupled receptors to their agonists induces a rapid decrease in their initial response. The goal of this study is to investigate alteration in SSTR2 by the treatment of SSTR agonist octreotide (OCT) in hepatocellular carcinoma (HCC) and the resulting consequence. Methods: Morphology, proliferation and cell cycle of the human HCC cell line (Bel7402) were evaluated. Effect of OCT on HCC growth and development was assessed in vivo. SSTR2 expression was measured by RT-PCR and detected by immunohistochemistry. Results: Short-term OCT treatment on Bel7402 cells barely changed cell proliferation and morphology, and no apoptosis was induced. The SSTR2 protein level was markedly decreased on Bel7402 cells after exposure to OCT. However, the weight of the HCC xenograft was significantly lower in the OCT treatment group as compared with the control group. In the rat hepatocarcinogenesis model, the mortality and incidence of HCC in the OCT treatment group were remarkably less than those in the control group. Long-term OCT treatment led to increased levels of both SSTR2 mRNA and protein in hepatocytes and HCC cells. Conclusion: Short-term OCT treatment could lead to SSTR2 desensitization, resulting in a reduced inhibitory effect on HCC by OCT. However, long-term OCT treatment effectively inhibited the development and growth of HCC probably via resensitization and upregulation of SSTR2.

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“…During the preneoplastic stage leading to HCC, SSTR gene expression levels in liver tissues appear to be altered regularly (9,34). SSTR expression levels increase with the progress of disease conditions, i.e.…”

Section: Discussionmentioning

confidence: 99%

Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment

Liu

Jiang

2013

Oncology Letters

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Liver resections for hepatocellular carcinoma (HCC) in cirrhotic livers are associated with early recurrence and poor survival. Somatostatin analogues (SSAs) have been reported to inhibit cell proliferation by interacting with specific somatostatin receptors (SSTRs) 2 and 5. The present study investigated whether SSTR expression in HCC was associated with the clinical outcome following octreotide long-acting release (LAR) treatment. Paired tumor and cirrhotic liver samples were obtained following a liver resection from 99 patients with stage I–II HCC and HBV-related cirrhosis. The expression of SSTR2 and 5 was assessed using quantitative (q)PCR and immunohistochemistry. The patients were classified into two groups, the high expression (n=47) and low expression (n=52) groups, based on the gene expression levels. The clinicopathological data and survival results of the two groups were compared. When compared with the surrounding cirrhotic tissue, the SSTR2 and 5 mRNA levels were significantly decreased in the HCC tissue. There were no significant differences between the groups with respect to the baseline characteristics. The tumor recurrence rate was significantly lower in the high expression group compared with that of the low expression group (63.83% vs. 82.69%; P=0.033). The 1-, 3- and 5-year disease-free and overall survival rates of the high expression group were 97, 89 and 71% and 98, 89 and 74%, respectively. The survival time of the members of the high expression group was longer compared with that of the low expression group. The multivariate analysis revealed that the TNM-7 stage and SSTR2 expression were independent prognostic factors for survival. In conclusion, SSTR mRNA expression correlated with survival in patients with early-stage hepatitis B virus (HBV)-related HCC who were treated with octreotide LAR following surgery. The inhibitory effects of SSAs on tumor growth may be mediated by SSTR expression.

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Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways

Cited by 20 publications

References 20 publications

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC

Mechanisms and Influence of Octreotide-Induced Regulation of Somatostatin Receptor 2 on Hepatocellular Carcinoma

Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment

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Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways

Cited by 20 publications

References 20 publications

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with 68Ga-DOTATOC

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with 68Ga-DOTATOC

Mechanisms and Influence of Octreotide-Induced Regulation of Somatostatin Receptor 2 on Hepatocellular Carcinoma

Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment

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Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC

Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with ⁶⁸Ga-DOTATOC