Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis

Kaemmer, Courtney A.; Umesalma, Shaikamjad; Maharjan, Chandra K.; Moose, Devon L.; Narla, Goutham; Mott, Sarah L.; Zamba, Gideon; Breheny, Patrick; Darbro, Benjamin W.; Bellizzi, Andrew M.; Henry, Michael D.; Quelle, Dawn E.

doi:10.1038/s41598-021-89866-1

Cited by 5 publications

(4 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lastly, the gut microbiota has become an active research field recently. β-sitosterol has been shown to exert the potential to modify the gut microbiota and even inhibit colorectal cancer progression [54][55][56]. The liposomal β-sitosterol generated and utilized in the current study are mainly taken up by the intestinal epithelium and may change the gut microbiota, which is worth further investigation.…”

Section: Discussionmentioning

confidence: 99%

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

et al. 2022

View full text Add to dashboard Cite

β-sitosterol (SITO) has been reported with anticancer effects; however, with poor bioavailability. The current study aimed to investigate whether liposomal encapsulated β-sitosterol (LS) has a better inhibition effect on tumor metastasis than β-sitosterol in a CT26/luc lung metastasis mouse model and the possible underlying mechanism. LS was liposomal-encapsulated SITO and was delivered to mice by oral gavage. The cell viability was determined by the MTT assay, and invasiveness of the tumor cells and related protein expression were evaluated with the invasion assay and Western blotting. For therapeutic efficacy evaluation, male BALB/c mice were treated with PBS, SITO, and LS once a day for 7 days prior to intravenous injections of CT26/luc cells; treatments were continued twice a week post-cell inoculation throughout the entire experiment. Tumor growth inhibition was monitored by bioluminescent imaging (BLI). IL-12, IL-18, and IFN-γ in the intestinal epithelium were determined by ELISA. The results show that LS treatment had a better invasion inhibition with lower cytotoxicity than SITO when the same dose was utilized. Notably, mice treated with LS significantly exhibited fewer metastases to the lungs and other tissues/organs compared with the Control and SITO groups. Additionally, the IL-12, IL-18, and IFN-γ levels were significantly increased in the LS-treated mice compared with the Control and SITO groups. The underlying mechanism may be through the inhibition of MMP-9 and elicitation of the antitumoral Th1 immune response, such as increasing CD4+ and CD8+ T cells, IL-12, IL-18, and IFN-γ.

show abstract

Section: Discussionmentioning

confidence: 99%

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Liver metastasis xenograft models were generated by injecting 1 million BON cells stably expressing the firefly luciferase gene (Kaemmer et al, 2021) in the spleen of an NSG mouse during surgery. Mice were given meloxicam daily for 7 days post-operation and monitored for signs of distress.…”

Section: Xenograft Modelsmentioning

confidence: 99%

“…Additionally, TE treated tumors appeared lighter in color and less vascularized compared to control tumors (Figure 6C). The effect of telotristat was tested on liver metastatic xenograft tumor models generated via intra-splenic injection of BON cells expressing a firefly luciferase reporter gene (Kaemmer et al, 2021) in NSG mice. Seven days-post injection, mice were randomized into treatment groups and given a vehicle control saline solution or 30 mg/kg telotristat by IP injections 5 times a week for the next 14 days.…”

Section: Bon Tph1 Knockdown Cells Form Smaller Tumors In Vivomentioning

confidence: 99%

Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growthin vivo

Tow

Tran

Borbon

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl in severe cases. Although the active drug telotristat can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor cell growth. The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition in vitro and in vivo using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting TPH1 were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates in vitro and in vivo, angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. TPH1 is highly expressed in SBNETs and many cancer types. TPH1 knockdown cells and telotristat treated cells showed similar growth rates as control cells in vitro. However, TPH1 knockdown cells formed smaller tumors in vivo and tumors were less vascularized. Although Tph1 inhibition with telotristat showed no effect on tumor cell growth in vitro, Tph1 inhibition reduced tumor formation in vivo. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs.

show abstract

“…Moreover, both BON-1 and NT-3 express somatostatin receptors and have been demonstrated to be highly sensitive to somatostatin analogues [339,340]. Recently, luciferase-expressing derivatives of BON-1 and QGP-1 cells were developed to enable bioluminescent imaging of pNET metastasis in vivo [343].…”

Section: Nt-3 Lymph Node Metastasis Of An Insulinomamentioning

confidence: 99%

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Maharjan

Ear

Tran

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

show abstract

Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis

Cited by 5 publications

References 41 publications

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

Inhibition of serotonin biosynthesis in neuroendocrine neoplasm suppresses tumor growthin vivo

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Contact Info

Product

Resources

About