Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human A549 induced tumours in mice treated with PCI-5002, PCI-5003, or control vehicle

ABSTRACT: We have demonstrated that water-soluble zinc ionophores can be administered to mice at relatively high doses and inhibit the growth of A549 lung cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice four hours after treatment confirmed that the activation of stress responsive genes occurs in vivo. These findings lead us to propose that the pharmacologic delivery of zinc to tumors using water solubilized ionophores is a potential approach to cancer therapy. Experiment Overall Design: 1.25 million A549 cells were injected subcutaneously/intramuscularly into the right hind flank of 6 week old CD-1 nude mice that had been irradiated with 4 Gy of total body irradiation from a 137Cs radiation source one day prior to tumor implantation. When the average size of tumors reached approximately 100 mm3, mice were randomized by tumor size to treatment groups, typically containing 6-8 mice per group. Tumor and body weight measurements were performed three times per week. Tumor volume was calculated using the equation V (mm3) = a x b2/2, where a is the largest diameter and b is the smallest diameter. No significant body weight loss was observed. To perform gene expression profiling, mice were treated intravenously with one dose (100 Î¼mol/kg) PCI-5002, PCI-5003, or control vehicle (4 mice per group) when the average A549 tumor size reached 500 mm3. After four hours, tumors were harvested and snap frozen immediately on dry ice. Tumor tissue was homogenized, and total RNA was isolated and subjected to analysis using Human Genome U133 Plus 2.0 Arrays as described above.

ORGANISM(S): Homo sapiens

SUBMITTER: Joseph Gerard Hacia

PROVIDER: E-GEOD-6962 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:All-trans retinoic acid (ATRA) is used in the treatment of Acute Promyelocytic Leukemia (APL) with exceptional results, inducing long-lasting remissions in 78% of the patients. In previous studies (Bolis M et al., Ann Oncol. 2017, 28:611; Centritto F et al., EMBO Mol Med. 2015, 7:950) we demonstrated the therapeutic potential of ATRA in the personalized treatment of breast cancer. The present study is aimed at providing pre-clinical evidence supporting the use of pharmacological strategies based on ATRA in the management of stomach cancer, a very heterogeneous type of tumor, which lacks effective therapeutic options other than surgery. To define the sensitivity of gastric cancer to the anti-proliferative action of ATRA, we used 27 cell-lines, recapitulating the heterogeneity of the tumor. Fourteen of these cell-lines are characterized by a G-DIF phenotype, while the remainders present with a G-INT phenotype. Each cell-line was exposed to increasing concentrations of ATRA and the growth-inhibitory effects of the retinoid were evaluated at 3, 6, and 9 days. The 27 cell-lines were ranked for their sensitivity to the retinoid with the “ATRA-score”, a continuous/quantitative index, which we developed. The results indicate that the cell-lines can be divided into 3 separate groups characterized by high, intermediate and low sensitivity to ATRA. No significant correlation between ATRA-sensitivity and the G-DIF or G-INT phenotype is observed in our panel of cell-lines. To support the results obtained with the cell-lines, we evaluated the anti-proliferative effects exerted by ATRA on short-term tissue slice cultures of primary tumors derived from 13 cases of stomach cancer, which we classified as G-DIF or G-INT following determination of the basal gene-expression profiles with the use of RNA-sequencing studies. The results obtained with the short-term tissue culture model confirm the data generated with the cell-lines. The whole genome RNA-sequencing studies performed in the cell-lines and short-term tissue cultures in basal conditions allowed us to define a model consisting of 42 genes whose expression is quantitatively correlated with ATRA-sensitivity. The model was used to predict the sensitivity of gastric cancer cases to ATRA using the TCGA dataset. The results obtained indicate that approximately 60% of the gastric cancer cases are predicted to be characterized by high/intermediate sensitivity to ATRA, regardless of the G-DIF or G-INT phenotype. In conclusion, our results support the concept that ATRA-based therapeutic strategies are likely to be beneficial in the majority of stomach cancer cases. In addition, we generate a gene-expression tool that may be used for the selection of ATRA-sensitive patients in the clinics.

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Transcription profiling of human A549 induced tumours in mice treated with PCI-5002, PCI-5003, or control vehicle

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