Novel aminochromone derivative inhibits tumor growth on xenograft model of lung cancer in mice

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

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535 POSTER Characterization of a fully human PDGFRa antibody that reduces tumor growth and stromal infiltration in a xenograft model of non-small cell lung cancer

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)72469-8 ◽

2008 ◽

Vol 6 (12) ◽

pp. 169

Author(s):

N. Laing ◽

B. McDermott ◽

S. Wen ◽

M. Pandya ◽

A.M. Mazzola ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Small Cell ◽

Small Cell Lung

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Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model

Scientific Reports ◽

10.1038/srep28057 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 7

Author(s):

Shan Xu ◽

Yuan Tian ◽

Yili Hu ◽

Nijia Zhang ◽

Sheng Hu ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Xenograft Model ◽

A549 Lung

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Effect of anamorelin/ONO-7643, a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19577 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19577-e19577

Author(s):

Robert Northrup ◽

Ken Kuroda ◽

Elizabeth Manning Duus ◽

Sheri Routt Barnes ◽

Tim Wiley ◽

...

Keyword(s):

Lung Cancer ◽

Body Weight ◽

Tumor Growth ◽

Food Consumption ◽

Nude Mice ◽

Receptor Agonist ◽

Xenograft Model ◽

Ghrelin Receptor ◽

Mouse Xenograft Model ◽

Ghrelin Receptor Agonist

e19577 Background: Anamorelin/ONO-7643 is an orally-active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related cachexia/anorexia. It displays both anabolic and orexigenic properties via its ghrelin and growth hormone (GH) secretagogue activity. However, increasing GH and insulin-like growth factor-1 (IGF-1) in cancer patients raises potential concerns of stimulating tumor growth. In this study, we investigated the effect of ghrelin and Anamorelin/ONO-7643 on tumor growth in a NSCLC xenograft model. Methods: On Day 1 (D1), 21 days after implanting A549 tumors, female nude mice were sorted into six groups (n=15/group) and administered ghrelin (2 mg/kg i.p.), Anamorelin/ONO-7643 (3, 10, or 30 mg/kg p.o.) or vehicles (saline i.p. or de-ionized water p.o.) for 28 days, starting on D3. Tumor growth, body weight, and food consumption were monitored. Mice used to assess plasma levels of murine GH (mGH) and IGF-1 (mIGF-1) were sorted into three groups (n=21/group) and treated for 28 days with ghrelin, the high dose of Anamorelin/ONO-7643 or vehicle (de-ionized water p.o.). Results: After 28 days of treatment, there was no difference in median tumor volumes (D30 values: 1008, 936, 1080, 666 and 847 mm3 for vehicle, ghrelin and Anamorelin/ONO-7643 at 3, 10 and 30 mg/kg, respectively). Ghrelin significantly increased mGH compared to controls, while Anamorelin/ONO-7643 modestly increased mGH. Peak mIGF-1 levels were slightly higher in animals given ghrelin or Anamorelin/ONO-7643 compared to vehicle, although not significantly. Anamorelin/ONO-7643 at 10 and 30 mg/kg/day showed a statistically significant (p<0.01) increase in body weight from D1 to D30 compared to control animals, with no change in food consumption. Ghrelin treatment had no effect on body weight or food consumption. Conclusions: Anamorelin/ONO-7643 or ghrelin treatment for 28 days had no effect on tumor growth in A549 tumor-bearing nude mice, despite increased mGH and a trend of increased mIGF-1. Anamorelin/ONO-7643 also significantly increased body weight at 10 and 30 mg/kg/day. These results support using ghrelin receptor agonist-based treatments in managing NSCLC-related cachexia/anorexia.

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Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three-dimensional lung cancer xenograft model

Cancer ◽

10.1002/cncr.24907 ◽

2010 ◽

Vol 116 (7) ◽

pp. 1739-1750 ◽

Cited By ~ 63

Author(s):

Xiaoyu Xu ◽

Glenn D. Prestwich

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Lysophosphatidic Acid ◽

Three Dimensional ◽

Xenograft Model ◽

Acid Antagonist ◽

Inhibition Of Tumor Growth

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Development and Characterization of Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases

10.1101/2020.06.02.130062 ◽

2020 ◽

Author(s):

Andrew M. Baschnagel ◽

Saakshi Kaushik ◽

Arda Durmaz ◽

Steve Goldstein ◽

Irene M. Ong ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Xenograft Model ◽

Small Cell ◽

Growth Delay ◽

Small Cell Lung

AbstractIntroductionThe purpose of this study was to establish and characterize a direct-from patient-derived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases.MethodsSurgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants into immunodeficient mice. Histology and DNA loci were compared between original tumor and subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant therapeutic targets were identified. Tumor growth rates were assessed following treatment with radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established.ResultsNine NSCLC brain metastases PDXs were established. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumor and subcutaneous and intracranial tumors. Short tandem repeat analysis demonstrated strong concordance between patient tumors and subsequent PDX passages. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples. Significant growth inhibition occurred with radiation, with selumetinib in tumors harboring KRAS G12C mutations and with savolitinib in a tumor with MET exon 14 skipping mutation. The combination of radiation and savolitinib resulted in significant tumor growth delay compared to radiation or savolitinib alone our MET exon 14 skipping mutation PDX. Early passage cell strains showed high consistency between patient and PDX tumors.ConclusionWe have established a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

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