scholarly journals Real-time, high-resolution imaging of tumor cells in genetically engineered and orthotopic models of thyroid cancer

2020 ◽  
Vol 27 (10) ◽  
pp. 529-539
Author(s):  
Xhesika Shanja-Grabarz ◽  
Anouchka Coste ◽  
David Entenberg ◽  
Antonio Di Cristofano
Keyword(s):  
Thyroid Cancer ◽  
High Resolution ◽  
Real Time ◽  
Tumor Cells ◽  
Mouse Models ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Genetically Engineered ◽  
Intravital Imaging ◽  
Anatomical Location

Genetically engineered and orthotopic xenograft mouse models have been instrumental for increasing our understanding of thyroid cancer progression and for the development of novel therapeutic approaches in a setting that is more physiologically relevant than the classical subcutaneous flank implants. However, the anatomical location of the thyroid gland precludes a non-invasive analysis at the cellular level of the interactions between tumor cells and the surrounding microenvironment and does not allow a real-time evaluation of the response of tumor cells to drug treatments. As a consequence, such studies have generally only relied on endpoint approaches, limiting the amount and depth of the information that could be gathered. Here we describe the development of an innovative approach to imaging specific aspects of thyroid cancer biology, based on the implantation of a permanent, minimally invasive optical window that allows high-resolution, multi-day, intravital imaging of the behavior and cellular dynamics of thyroid tumors in the mouse. We show that this technology allows visualization of fluorescently tagged tumor cells both in immunocompetent, genetically engineered mouse models of anaplastic thyroid cancer (ATC) and in immunocompromised mice carrying orthotopic implanted human or mouse ATC cells. Furthermore, the use of recipient mice in which endothelial cells and macrophages are fluorescently labeled allows the detection of the spatial and functional relationship between tumor cells and their microenvironment. Finally, we show that ATC cells expressing a fluorescent biosensor for caspase 3 activity can be effectively utilized to evaluate, in real-time, the efficacy and kinetics of action of novel small molecule therapeutics. This novel approach to intravital imaging of thyroid cancer represents a platform that will allow, for the first time, the longitudinal, in situ analysis of tumor cell responses to therapy and of their interaction with the microenvironment.

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

scholarly journals Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 367 ◽  
Author(s):  
Melnik ◽  
Sahana ◽  
Corydon ◽  
Kopp ◽  
Nassef ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Expression Patterns ◽  
Three Dimensional ◽  
Signal Pathways ◽  
Dependent Manner ◽  
Spheroid Formation ◽  
Mesenchymal Transition

Detachment and the formation of spheroids under microgravity conditions can be observed with various types of intrinsically adherent human cells. In particular, for cancer cells this process mimics metastasis and may provide insights into cancer biology and progression that can be used to identify new drug/target combinations for future therapies. By using the synthetic glucocorticoid dexamethasone (DEX), we were able to suppress spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells that were exposed to altered gravity conditions on a random positioning machine. DEX inhibited the growth of three-dimensional cell aggregates in a dose-dependent manner. In the first approach, we analyzed the expression of several factors that are known to be involved in key processes of cancer progression such as autocrine signaling, proliferation, epithelial–mesenchymal transition, and anoikis. Wnt/β-catenin signaling and expression patterns of important genes in cancer cell growth and survival, which were further suggested to play a role in three-dimensional aggregation, such as NFKB2, VEGFA, CTGF, CAV1, BCL2(L1), or SNAI1, were clearly affected by DEX. Our data suggest the presence of a more complex regulation network of tumor spheroid formation involving additional signal pathways or individual key players that are also influenced by DEX.

scholarly journals Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

2020 ◽  
Vol 35 (1_suppl) ◽  
pp. 8-11 ◽  
Author(s):  
Paola Nisticò ◽  
Gennaro Ciliberto
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Development ◽  
Short Paper ◽  
Great Relevance ◽  
Cellular Components ◽  
The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

scholarly journals How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

2011 ◽  
Vol 29 (16) ◽  
pp. 2273-2281 ◽  
Author(s):  
Katerina Politi ◽  
William Pao
Keyword(s):  
Mouse Models ◽  
Cancer Biology ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Genetically Engineered Mouse Models ◽  
Human Cancers ◽  
Chemically Induced

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review.

scholarly journals Mouse Models of Follicular and Papillary Thyroid Cancer Progression

2012 ◽  
Vol 2 ◽  
Author(s):  
Marika A. Russo ◽  
Valeria G. Antico Arciuch ◽  
Antonio Di Cristofano
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Mouse Models ◽  
Cancer Progression ◽  
Papillary Thyroid

Abstract 3983: Real-time imaging of human thyroid cancer progression in a fluorescent orthotopic nude mouse model

2010 ◽  
Author(s):  
Hop S. Tran Cao ◽  
Sharmeela Kaushal ◽  
Cynthia S. Snyder ◽  
Weg M. Ongkeko ◽  
Robert M. Hoffman ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Real Time ◽  
Nude Mouse ◽  
Cancer Progression ◽  
Human Thyroid ◽  
Nude Mouse Model ◽  
Real Time Imaging

scholarly journals Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 892 ◽  
Author(s):  
Claire Vennin ◽  
David Herrmann ◽  
Morghan C. Lucas ◽  
Paul Timpson
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Disease Progression ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Normal Tissue ◽  
Intravital Imaging ◽  
Cancer Development ◽  
Recent Advances ◽  
Insight Into

Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression.

scholarly journals Tumor expressed CD95 causes suppression of anti-tumor activity of NK cells in a model of triple negative breast cancer

2021 ◽  
Author(s):  
Abdul S. Qadir ◽  
Jean Philippe Guégan ◽  
Christophe Ginestier ◽  
Assia Chaibi ◽  
Alban Bessede ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nk Cells ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mouse Models ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Therapy ◽  
Genetically Engineered

AbstractThe apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. Stimulation by its cognate ligand CD95L on many cancer cells increases their growth, motility, ability to invade and/or their cancer stemness. Using genetically engineered mouse models of ovarian and liver cancer, we previously reported that deletion of CD95 in the tumor cells strongly reduced their ability to grow in vivo [1, 2]. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer cells prevents tumor growth by modulating the immune landscape. CD95 deficient but not wild-type tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by NK cells and does not involve CD8+ T cells. On the other hand, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities providing a new target for immune therapy.

scholarly journals The Mysterious Food-Entrainable Oscillator: Insights from Mutant and Engineered Mouse Models

2018 ◽  
Vol 33 (5) ◽  
pp. 458-474 ◽  
Author(s):  
Julie S. Pendergast ◽  
Shin Yamazaki
Keyword(s):  
Mouse Models ◽  
Energy Homeostasis ◽  
Genetically Engineered ◽  
Anatomical Location ◽  
Restricted Feeding ◽  
Genetically Engineered Mouse Models ◽  
Experimental Protocols ◽  
Free Running ◽  
Anticipatory Activity ◽  
Molecular Components

The food-entrainable oscillator (FEO) is a mysterious circadian clock because its anatomical location(s) and molecular timekeeping mechanism are unknown. Food anticipatory activity (FAA), which is defined as the output of the FEO, emerges during temporally restricted feeding. FAA disappears immediately during ad libitum feeding and reappears during subsequent fasting. A free-running FAA rhythm has been observed only in rare circumstances when food was provided with a period outside the range of entrainment. Therefore, it is difficult to study the circadian properties of the FEO. Numerous studies have attempted to identify the critical molecular components of the FEO using mutant and genetically engineered mouse models. Herein we critically review the experimental protocols and findings of these studies in mouse models. Several themes emerge from these studies. First, there is little consistency in restricted feeding protocols between studies. Moreover, the protocols were sometimes not optimal, resulting in erroneous conclusions that FAA was absent in some mouse models. Second, circadian genes are not necessary for FEO timekeeping. Thus, another noncanonical timekeeping mechanism must exist in the FEO. Third, studies of mouse models have shown that signaling pathways involved in circadian timekeeping, reward (dopaminergic), and feeding and energy homeostasis can modulate, but are not necessary for, the expression of FAA. In sum, the approaches to date have been largely unsuccessful in discovering the timekeeping mechanism of the FEO. Moving forward, we propose the use of standardized and optimized experimental protocols that focus on identifying genes that alter the period of FAA in mutant and engineered mouse models. This approach is likely to permit discovery of molecular components of the FEO timekeeping mechanism.

Sign in / Sign up

Export Citation Format

Share Document