Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

Jung, Joohee

doi:10.5487/tr.2014.30.1.001

Cited by 112 publications

(71 citation statements)

References 31 publications

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“…Altogether, these in vivo results confirmed that the organotypic setting mimicking the initial stages of tumor development (low collagen I ECM), indeed, successfully predicted the increased ability of CSCs to induce a hyper-proliferative, blood-conductive vascular network in the primary tumor, growing ectotopically (without signs of local infiltration and/or distant metastases) in an early-stage xenograft tumor model [39].…”

Section: Cscs In Nude Mice Develop Proliferating and Hypervascular Tusupporting

confidence: 66%

Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome

et al. 2018

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Its aggressiveness is driven by an intense fibrotic desmoplastic reaction in which the increasingly collagen I-rich extracellular matrix (ECM) and several cell types, including cancer stem cells (CSCs), create a tumor-supportive environment. However, how ECM composition regulates CSC dynamics and their relationship with the principle parenchymal tumor population to promote early invasive growth is not yet characterized. For this, we utilized a platform of 3D organotypic cultures composed of laminin-rich Matrigel, representative of an early tumor, plus increasing concentrations of collagen I to simulate malignant stroma progression. As ECM collagen I increases, CSCs progress from a rapidly growing, vascular phenotype to a slower growing, avascular phase, while maintaining their endothelial-like gene signatures. This transition is supported autocrinically by the CSCs and paracrinically by the parenchymal cells via their ECM-dependent secretomes. Indeed, when growing on an early tumor ECM, the CSCs are dedicated toward the preparation of a vascular niche by (a) activating their growth program, (b) secreting high levels of proangiogenic factors which stimulate both angiogenesis and vasculogenic mimicry, and (c) overexpressing VEGFR-2, which is activated by VEGF secreted by both the CSC and parenchymal cells. On Matrigel, the more differentiated parenchymal tumor cell population had reduced growth but a high invasive capacity. This concerted high local invasion of parenchymal cells into the CSC-derived vascular network suggests that a symbiotic relationship between the parenchymal cells and the CSCs underlies the initiation and maintenance of early PDAC infiltration and metastasis.

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Section: Cscs In Nude Mice Develop Proliferating and Hypervascular Tusupporting

confidence: 66%

Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome

et al. 2018

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“…To date, no preclinical tumor model perfectly recapitulates human disease because of differences across species, tumor environment, and immune response [29]. Furthermore, it has been shown that the site of the tumor implantation can be critical, since tumor-host interactions and tumor microenvironment can modulate tumor development, disease progression, and response to therapy [30, 31].…”

Section: Discussionmentioning

confidence: 99%

Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location

et al. 2016

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PURPOSE Preclinical studies of hypoxia are generally done using ectopic xenograft tumors, which behave differently from human tumors. Our previous findings have shown that subcutaneously implanted lung tumors exhibit more hypoxia than their orthotopic implanted or spontaneous K-ras induced counterparts. We hypothesize that differences in hypoxia are due to site-specific differences in vascularity and perfusion. PROCEDURES To compare the presence and functionality of vessels in these tumor models, we studied vascular perfusion in vivo in real time. RESULTS Orthotopically implanted and spontaneous K-ras induced lung tumors showed elevated perfusion, demonstrating vasculature functionality. Little contrast agent uptake was observed within the subcutaneously implanted tumors, indicating vascular dysfunction. These findings were corroborated at the microscopic level with Hoechst33342 and Meca-32 staining. CONCLUSIONS From these observations we concluded that differences in hypoxia in experimental models is related to vessel perfusion. Thus, appropriate selection of preclinical lung tumor models is essential for the study of hypoxia, angiogenesis and therapies targeting these phenomena.

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“…4) An improved understanding of the potential of the benzo[c]phenanthridines can be achieved by xenograft studies, which are used to evaluate therapeutic efficacy and toxicity in anticancer drug development. [50] Experimental Section Chemistry All chemicals were commercially available and were purchased from either Acros, Fluka/Sigma-Aldrich, Lancaster,o rM erck. Spectroscopy:p roton and carbon NMR spectra were recorded at 300 MHz ( 1 H) and 75.5 MHz ( 13 C) at 300 Ku sing aB ruker ARX 300 spectrometer,w ith tetramethylsilane as internal standard.…”

Section: Discussionmentioning

confidence: 99%

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

Clement¹,

Girreser²,

Steinhauer³

et al. 2016

ChemMedChem

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The synthesis of various new structures of a library of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines (BP) and 11-substituted 6-aminobenzo[c]phenanthridines (BP-D) is presented. These structures, further synthetic modifications, and the preparation of follow-up products which delivered about 40 new derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison of NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines. NCI-COMPARE studies helped to suggest the modes of action of the highly active antiproliferative drugs. These findings are supported by in vitro biological investigations showing either inhibition of tubulin polymerization and depolymerization or topoisomerase inhibition. Together with physicochemical parameters of the drug candidates, structure-activity relationships are critically discussed. Tubulin interaction or inhibition of topoisomerase I and IIα/β activity are two rationales that can explain the antiproliferative activity observed in the NCI 60 DTP human tumor cell line screen. However, it can also be reasonably assumed that these compounds address several targets, thus prohibiting the identification of simple structure-activity relationships. The new structures described herein are thought to act as so-called multitarget drugs, thus being of special interest in the area of multidrug resistance.

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Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

Cited by 112 publications

References 31 publications

Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome

Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome

Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

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