Detecting metastatic tumors after γ-irradiation using longitudinal molecular imaging and gene expression profiling of metastatic tumor nodules
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ABSTRACT: Microarray analysis in the mouse metastatic tumor after ɣ-irradiation(ɣ-IR): non-irradiated primary tumor vs. radiated primary tumor vs. metastatic tumor after ɣ-irradiation Metastatic tumors in C6-L (rat glioma cells ) xenografted mice were studied after local treatment with fractionated γ-IR. To accurately detect the metastatic nodules after γ-IR, we observed the effect of γ-IR on distant metastatic tumor growth. Metastatic nodules after γ-IR indicated extensive colonization of C6-L cells in the lungs within 6 weeks after γ-IR. Identified and described the molecular events occurring after γ-IR through gene expression profiling to elucidate genetic changes (differentially expressed genes between the γ-IR primary tumors vs. non-γ-IR primary tumors and metastatic lung nodules vs. γ-IR primary tumors). We investigated the change of gene expression profile in the γ-IR primary tumors vs. non-γ-IR primary tumors and metastatic lung nodules vs. γ-IR primary tumors in rat glioma (C6-L cell) xenograft model.
Project description:Microarray analysis in the mouse metastatic tumor after ɣ-irradiation(ɣ-IR): non-irradiated primary tumor vs. radiated primary tumor vs. metastatic tumor after ɣ-irradiation Metastatic tumors in C6-L (rat glioma cells ) xenografted mice were studied after local treatment with fractionated γ-IR. To accurately detect the metastatic nodules after γ-IR, we observed the effect of γ-IR on distant metastatic tumor growth. Metastatic nodules after γ-IR indicated extensive colonization of C6-L cells in the lungs within 6 weeks after γ-IR. Identified and described the molecular events occurring after γ-IR through gene expression profiling to elucidate genetic changes (differentially expressed genes between the γ-IR primary tumors vs. non-γ-IR primary tumors and metastatic lung nodules vs. γ-IR primary tumors).
Project description:To examine whether the local carbon ion radiotherapy affects the characteristics of the metastatic tumors, the expression profiles of the primary tumors and the lung metastases were studied in a mouse squamous cell carcinoma model by applying local radiotherapy with no irradiation (negative control), gamma-ray irradiation (reference beam), and carbon-ion irradiation. Keywords: mouse, squamous cell carcinoma, primary tumor, lung metastases, radiotherapy, carbon ion, gamma ray A highly metastatic mouse squamous cell carcinoma NR-S1 was implanted into the hind leg of synergetic C3H/HeNrs mice and irradiated with 5 Gy of carbon ion beam. 8 Gy of gamma ray was used as a reference beam. At 2 weeks after the irradiation, the lung tissue was sampled. In order to collect samples of primary tumors, the tumors were implanted in other mice and irradiated in the same manner, and the primary tumors were collected at 1 week after the irradiation. The tumor cells of the primary and metastatic tumors were collected by laser microdissection, and oligonucleotide microarray analysis of the irradiated primary tumors and the metastatic tumors were all performed in comparison to the non-irradiated primary tumor by two-color methods.
Project description:The immune system sustains inflammation, and can occasionally inhibit tumor development. Conversely, chronic inflammation positively contributes to the development of cancer. Furthermore, it was revealed that the large number of macrophages and haematopoietic progenitor cells accumulate in response to primary tumors in pre-metastatic lungs. However, the relationship between the inflammation-like state induced by primary tumors in pre-metastatic phase and the migration of tumor cells in metastasis is not well understood. Here we analyzed transcriptional change of the lungs by pre-metastatic stimuli. Experiment Overall Design: We examined the lungs derived from mice that had been injected with tumor cells into the back subcutaneously. This model mimics pre-metastatic lungs responding to a primary tumor before tumor cells reach the lungs.
Project description:Genomic changes in low and highly metastatic A549 cells were analyzed by 500K SNP arrays. A large number of genomic alterations were present in A549 cells but no significant differences were observed between the low or highly metastatic A549 cell lines. We generated a NSCLC line with highly increased propensity to form tumor nodules in murine lungs after intravenous injections. Extravasation and growth at a distant site are important parts of the metastatic process and we regarded these as a surrogate marker for in vivo aggressiveness and potential metastatic capability. A549 lung asdenocarcimona cell line with initially low metastatic potential was used for this purpose; these cells formed multiple small nodules in NOD/SCID mice after first i.v.-injection, round 1 (R1). Removal of tumor nodules from the lungs and subsequent re-injection led to a rapid increase in metastatic capacity. A highly aggressive phenotype which was stable over time was evident after three rounds (R3) of in vivo selection for the A549 cell line.
Project description:We report that metastasis in an autochthonous mouse model of sarcoma is driven by a single clone in the primary tumor. We performed RNA-seq comparing the gene expression profiles of the metastatic clones (MC) to matched non-metastatic clones (non-MC) from the same tumor for multiple tumors. RNA from lung metastases (Lung-Met) of matched tumors are sequenced as well.
Project description:Metastasis is the primary cause of cancer-related mortality and the mechanistically least well understood step of the tumor progression cascade. Employing surgical preclinical metastasis models, we show here that small primary tumors reprogram the body’s vascular endothelium to alter systemic homeostasis and to condition the premetastatic niche for metastatic colonization. Endothelial cells thereby serve as an amplifier of tumor-induced instructive signals. The combined endothelial transcriptomic and serum proteomic screen identified the TGFß pathway signaling specifier LRG1 as an early vascular niche instructor of metastatic colonization. Adjuvant LRG1 inhibition to primary tumor-resected mice delayed metastatic growth and increased overall survival. The study has thereby established the premetastatic systems map of primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis
Project description:The immune system sustains inflammation, and can occasionally inhibit tumor development. Conversely, chronic inflammation positively contributes to the development of cancer. Furthermore, it was revealed that the large number of macrophages and haematopoietic progenitor cells accumulate in response to primary tumors in pre-metastatic lungs. However, the relationship between the inflammation-like state induced by primary tumors in pre-metastatic phase and the migration of tumor cells in metastasis is not well understood. Here we analyzed transcriptional change of the lungs by pre-metastatic stimuli. Keywords: Gene expression analysis of pre-metastatic lungs
Project description:Prostate cancer is characterized by heterogeneity in the clinical course that often does not to correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. The metastatic samples are highly heterogeneous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodeling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer. Experiment Overall Design: Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors.
Project description:Detecting metastatic tumors after γ-irradiation using longitudinal molecular imaging and gene expression profiling of metastatic tumor nodules