scholarly journals Mouse Models for Studying Oral Cancer: Impact in the Era of Cancer Immunotherapy

2018 ◽  
Vol 97 (6) ◽  
pp. 683-690 ◽  
Author(s):  
J.J. Luo ◽  
C.D. Young ◽  
H.M. Zhou ◽  
X.J. Wang
Keyword(s):  
Oral Cancer ◽  
Cancer Immunotherapy ◽  
Cancer Genetics ◽  
Tumor Stroma ◽  
Model Systems ◽  
Therapeutic Interventions ◽  
In Vivo Model ◽  
Oral Cancer Patients ◽  
The Impact

Model systems for oral cancer research have progressed from tumor epithelial cell cultures to in vivo systems that mimic oral cancer genetics, pathological characteristics, and tumor-stroma interactions of oral cancer patients. In the era of cancer immunotherapy, it is imperative to use model systems to test oral cancer prevention and therapeutic interventions in the presence of an immune system and to discover mechanisms of stromal contributions to oral cancer carcinogenesis. Here, we review in vivo mouse model systems commonly used for studying oral cancer and discuss the impact these models are having in advancing basic mechanisms, chemoprevention, and therapeutic intervention of oral cancer while highlighting recent discoveries concerning the role of immune cells in oral cancer. Improvements to in vivo model systems that highly recapitulate human oral cancer hold the key to identifying features of oral cancer initiation, progression, and invasion as well as molecular and cellular targets for prevention, therapeutic response, and immunotherapy development.

scholarly journals Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing

2019 ◽  
Vol 41 (3) ◽  
pp. 334-344
Author(s):  
Amrendra Mishra ◽  
Fatemeh Emamgholi ◽  
Zulrahman Erlangga ◽  
Björn Hartleben ◽  
Kristian Unger ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Genetic Alterations ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Precision Oncology ◽  
Kras Mutations ◽  
Genomic Deletions ◽  
The Impact

Abstract Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

scholarly journals High Expression of KLF10 Is Associated with Favorable Survival in Patients with Oral Squamous Cell Carcinoma

Medicina ◽  
2020 ◽  
Vol 57 (1) ◽  
pp. 17
Author(s):  
Chung-Min Yeh ◽  
Yi-Ju Lee ◽  
Po-Yun Ko ◽  
Yueh-Min Lin ◽  
Wen-Wei Sung
Keyword(s):  
Survival Rate ◽  
Oral Cancer ◽  
Cancer Patients ◽  
Protective Factor ◽  
Female Gender ◽  
Vital Role ◽  
Cancer Stage ◽  
Independent Prognostic Marker ◽  
Oral Cancer Patients ◽  
The Impact

Background and objectives: Krüppel-like transcription factor 10 (KLF10) plays a vital role in regulating cell proliferation, including the anti-proliferative process, activation of apoptosis, and differentiation control. KLF10 may also act as a protective factor against oral cancer. We studied the impact of KLF10 expression on the clinical outcomes of oral cancer patients to identify its role as a prognostic factor in oral cancer. Materials and Methods: KLF10 immunoreactivity was analyzed by immunohistochemical (IHC) stain analysis in 286 cancer specimens from primary oral cancer patients. The prognostic value of KLF10 on overall survival was determined by Kaplan–Meier analysis and the Cox proportional hazard model. Results: High KLF10 expression was significantly associated with male gender and betel quid chewing. The 5-year survival rate was greater for patients with high KLF10 expression than for those with low KLF10 expression (62.5% vs. 51.3%, respectively; p = 0.005), and multivariate analyses showed that high KLF10 expression was the only independent factor correlated with greater overall patient survival. The significant correlation between high KLF10 expression and a higher 5-year survival rate was observed in certain subgroups of clinical parameters, including female gender, non-smokers, cancer stage T1, and cancer stage N0. Conclusions: KLF10 expression, detected by IHC staining, could be an independent prognostic marker for oral cancer patients.

In Vitro and In Vivo Model Systems for the Study of Allergic and Inflammatory Disorders in Man

CHEST Journal ◽  
1985 ◽  
Vol 87 (5) ◽  
pp. 162S-164S ◽  
Author(s):  
Stephen P. Peters ◽  
Robert M. Naclerio ◽  
Alkis Togias ◽  
Robert P. Schleimer ◽  
Donald W. MacGlashan ◽  
...  
Keyword(s):  
Model Systems ◽  
In Vivo Model ◽  
Inflammatory Disorders

scholarly journals Diet, Obesity, and Cancer Progression: Are Adipocytes the Link?

2013 ◽  
Vol 6 ◽  
pp. LPI.S10871 ◽  
Author(s):  
Paul Toren ◽  
Benjamin C. Mora ◽  
Vasundara Venkateswaran
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Model Systems ◽  
In Vivo Model ◽  
Diet Induced Obesity ◽  
Breast And Prostate Cancer ◽  
Obesity And Cancer

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1485
Author(s):  
Aina Venkatasamy ◽  
Eric Guerin ◽  
Anais Blanchet ◽  
Christophe Orvain ◽  
Véronique Devignot ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Real Time ◽  
Histone Deacetylase Inhibitors ◽  
Structural Changes ◽  
Histone Deacetylation ◽  
In Vivo Model ◽  
Specific Cell ◽  
The Impact

The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an “epithelial cell like” signature while SAHA favored a “mesenchymal cell like” one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.

scholarly journals The TRH Gene Is Regulated by Thyroid Hormone at the Level of Transcription in Vivo

2010 ◽  
Vol 31 (1) ◽  
pp. 136-136
Author(s):  
Michelle L. Sugrue ◽  
Kristen R. Vella ◽  
Crystal Morales ◽  
Marisol E. Lopez ◽  
Anthony N. Hollenberg
Keyword(s):  
Thyroid Hormone ◽  
Genomic Region ◽  
Model System ◽  
Model Systems ◽  
In Vivo Model ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Normal Production

ABSTRACT The expression of the TRH gene in the paraventricular nucleus (PVH) of the hypothalamus is required for the normal production of thyroid hormone (TH) in rodents and humans. In addition, the regulation of TRH mRNA expression by TH, specifically in the PVH, ensures tight control of the set point of the hypothalamic-pituitary-thyroid axis. Although many studies have assumed that the regulation of TRH expression by TH is at the level of transcription, there is little data available to demonstrate this. We used two in vivo model systems to show this. In the first model system, we developed an in situ hybridization (ISH) assay directed against TRH heteronuclear RNA to measure TRH transcription directly in vivo. We show that in the euthyroid state, TRH transcription is present both in the PVH and anterior/lateral hypothalamus. In the hypothyroid state, transcription is activated in the PVH only and can be shut off within 5 h by TH. In the second model system, we employed transgenic mice that express the Cre recombinase under the control of the genomic region containing the TRH gene. Remarkably, TH regulates Cre expression in these mice in the PVH only. Taken together, these data affirm that TH regulates TRH at the level of transcription in the PVH only and that genomic elements surrounding the TRH gene mediate its regulation by T3. Thus, it should be possible to identify the elements within the TRH locus that mediate its regulation by T3 using in vivo approaches.

scholarly journals IKKβ slows Huntington’s disease progression in R6/1 mice

2019 ◽  
Vol 116 (22) ◽  
pp. 10952-10961 ◽  
Author(s):  
Joseph Ochaba ◽  
Gianna Fote ◽  
Marketta Kachemov ◽  
Soe Thein ◽  
Sylvia Y. Yeung ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Degeneration ◽  
Neuronal Injury ◽  
Therapeutic Interventions ◽  
Striatal Neurons ◽  
Microglial Response ◽  
Relationship Of ◽  
The Impact

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

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