Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT

Elf, Anna-Karin; Johanson, Viktor; Marin, Ida; Bergström, Anders; Nilsson, Ola; Svensson, Johanna; Wängberg, Bo; Bernhardt, Peter; Elias, Erik

doi:10.3390/cancers13092035

Cited by 8 publications

(11 citation statements)

References 30 publications

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“…SSTR2, as a G protein-coupled cell surface receptor, can be activated by extracellular ligands, which leads to the inhibition of cell proliferation ( Lechner et al, 2021 ). Precious studies demonstrated that SSTR2 might serve as a molecular target in the diagnosis and treatment of thyroid cancer ( Thakur et al, 2021 ), small intestinal neuroendocrine tumor ( Elf et al, 2021 ), and neuroendocrine tumors ( Si et al, 2021 ). VIP can provide protection from apoptosis in tumorigenesis ( Sastry et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring Immune-Related Prognostic Signatures in the Tumor Microenvironment of Colon Cancer

Cao

Ba³

et al. 2022

Front. Genet.

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Background: Colon cancer is a common malignant tumor with poor prognosis. The aim of this study is to explore the immune-related prognostic signatures and the tumor immune microenvironment of colon cancer.Methods: The mRNA expression data of TCGA-COAD from the UCSC Xena platform and the list of immune-related genes (IRGs) from the ImmPort database were used to identify immune-related differentially expressed genes (DEGs). Then, we constructed an immune-related risk score prognostic model and validated its predictive performance in the test dataset, the whole dataset, and two independent GEO datasets. In addition, we explored the differences in tumor-infiltrating immune cell types, tumor mutation burden (TMB), microsatellite status, and expression levels of immune checkpoints and their ligands between the high-risk and low-risk score groups. Moreover, the potential value of the identified immune-related signature with respect to immunotherapy was investigated based on an immunotherapeutic cohort (Imvigor210) treated with an anti-PD-L1 agent.Results: Seven immune-related DEGs were identified as prognostic signatures. The areas under the curves (AUCs) of the constructed risk score model for overall survival (OS) were calculated (training dataset: 0.780 at 3 years, 0.801 at 4 years, and 0.766 at 5 years; test dataset: 0.642 at 3 years, 0.647 at 4 years, and 0.629 at 5 years; and the whole dataset: 0.642 at 3 years, 0.647 at 4 years, and 0.629 at 5 years). In the high-risk score group of the whole dataset, patients had worse OS, higher TMN stages, advanced pathological stages, and a higher TP53 mutation rate (p < 0.05). In addition, a high level of resting NK cells or M0 macrophages, and high TMB were significantly related to poor OS (p < 0.05). Also, we observed that high-risk score patients had a high expression level of PD-L1, PD-1, and CTLA-4 (p < 0.05). The patients with high-risk scores demonstrated worse prognosis than those with low-risk scores in multiple datasets (GSE39582: p = 0.0023; GSE17536: p = 0.0008; immunotherapeutic cohort without platinum treatment: p = 0.0014; immunotherapeutic cohort with platinum treatment: p = 0.0027).Conclusion: We developed a robust immune-related prognostic signature that performed great in multiple cohorts and explored the characteristics of the tumor immune microenvironment of colon cancer patients, which may give suggestions for the prognosis and immunotherapy in the future.

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Section: Discussionmentioning

confidence: 99%

Exploring Immune-Related Prognostic Signatures in the Tumor Microenvironment of Colon Cancer

Cao

Ba³

et al. 2022

Front. Genet.

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“…This heterogeneity is also pronounced in their endocrine activities and tumor growth, possibly because GI-NETs originate from a variety of neuroendocrine cells located in different sites [10]. Almost all GI-NETs have been reported to express somatostatin receptors (SSTRs), and their expression profiles have also been known to be heterogeneous [7,8,11].…”

Section: Introductionmentioning

confidence: 99%

“…Various scoring systems of SSTR2 immunoreactivity based on eyeball analysis, such as Volante score [18,19] and Immunoreactivity Score [11,20], have been proposed in order to yield a more reproducible and subjective interpretation of results toward establishing a better correlation between SSTR2 immunohistochemistry results and SSAs' therapeutic efficacy. However, these attempts have been mostly reported in PanNETs, not in GI-NETs.…”

Section: Introductionmentioning

confidence: 99%

Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors

Watanabe

Fujishima

Komoto

et al. 2022

Cancers

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Somatostatin analogues (SSAs) are widely used to treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Somatostatin receptor 2 (SSTR2) immunoreactivity serves as a predictive marker of the therapeutic efficacy of SSAs in pancreatic NETs. However, SSTR2 expression profiles in tumor cells and their association with the therapeutic efficacy of SSAs remains virtually unknown in gastrointestinal NETs (GI-NETs). Therefore, we evaluated the association between SSTR2 immunoreactivity and embryological origin and proliferative activity in 132 resected surgical tissues of GI-NETs. The correlation between SSAs’ therapeutic efficacy and SSTR2 immunoreactivity was evaluated in 14 GI-NETs treated with SSAs. SSTR2 immunoreactivity was evaluated using Volante scores, immunoreactive scores, and digital image analysis (DIA). SSTR2 immunoreactivity was significantly negatively and positively correlated with the Ki-67 labeling index in foregut and hindgut NETs, respectively. In the normal mucosa, neuroendocrine cells in the rectum had significantly lower positive rates of SSTR2 than those in the stomach and duodenum. SSTR2 expression profiles in GI-NETs could differ by primary sites, while the difference of those between foregut and hindgut NETs might be derived from the SSTR2 status of normal neuroendocrine cell counterparts. In addition, DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs.

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“…Neuroendocrine tumors are tumors of neuroendocrine cells, usually associated with high expression of somatostatin receptor subtype 2 (SSTR2) [1]. 68 Ga-DOTA-D Phe 1 ,Tyr 3 -octreotate ( 68 Ga-DOTATATE), a somatostatin analogue with high a nity for SSTR2, has been used in the imaging of neuroendocrine tumors [2]. Once SSTR2 expression is con rmed by 68 Ga-DOTATATE based imaging, the same SSTR2 analog, DOTATATE, can be attached to the therapeutic radioisotope ( 177 Lu, typically) and be used for molecular targeted therapy, which is called peptide receptor radionuclide therapy (PRRT) [3].…”

Section: Introductionmentioning

confidence: 99%

“…68 Ga-DOTA-D Phe 1 ,Tyr 3 -octreotate ( 68 Ga-DOTATATE), a somatostatin analogue with high a nity for SSTR2, has been used in the imaging of neuroendocrine tumors [2]. Once SSTR2 expression is con rmed by 68 Ga-DOTATATE based imaging, the same SSTR2 analog, DOTATATE, can be attached to the therapeutic radioisotope ( 177 Lu, typically) and be used for molecular targeted therapy, which is called peptide receptor radionuclide therapy (PRRT) [3]. The uptake of DOTATATE can be observed not only in tumor tissues, but also in normal organs, such as liver and spleen.…”

Section: Introductionmentioning

confidence: 99%

Identification of Genes Related to 68Ga-DOTATATE Organ Distribution in Homo Sapiens

Huang

2021

Preprint

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Purpose 68Ga-DOTATATE is a somatostatin analogue that has been used for imaging neuroendocrine tumours. However, there is nonspecific uptake in some organs, and the reasons for that are not clear. The aim of the study is to outline the dynamic distribution pattern of 68Ga-DOTATATE in human body, and identify the genes responsible for 68Ga-DOTATATE uptake by bioinformatics analysis.Methods 68Ga-DOTATATE PET/CT was performed in 32 patients, and dynamic total-body PET scanning was performed with uEXPLORER. The gene expression datasets of human organs were downloaded from the Human Protein Atlas. WGCNA analysis was performed to screen the potential genes related to 68Ga-DOTATATE. BindingDB, SEA and SwissTargetPrediction databases were used to predict the potential binding proteins of DOTATATE based on molecular structure. Results Dynamic total-body PET scanning showed that 68Ga-DOTATATE uptake was not consistent with expression of SSTR2 in human organs. WGCNA analysis revealed 800 genes whose expression level was positively correlated to 68Ga-DOTATATE uptake. According to the molecular structure of DOTATATE, 135 proteins with potential binding ability to DOTATATE were screened by analysis based on drug database. Based on the results of the above two parts, 8 proteins were finally obtained, respectively AVPR1A, EPHA8, EPHB4, OPRL1, SSTR2, SSTR5, ST3GAL1 and NPY1R, which had potential binding possibility with DOTATATE, and their expression was positively correlated with 68Ga-DOTATATE uptake.Conclusion WGCNA analysis was combined with the drug database to obtain new potential binding targets of DOTATATE. The bioinformatics approach developed in this study could potentially be used to discover new potential binding targets for molecular imaging agents.

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Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT

Cited by 8 publications

References 30 publications

Exploring Immune-Related Prognostic Signatures in the Tumor Microenvironment of Colon Cancer

Exploring Immune-Related Prognostic Signatures in the Tumor Microenvironment of Colon Cancer

Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors

Identification of Genes Related to 68Ga-DOTATATE Organ Distribution in Homo Sapiens

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