Project description:Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtypes. Various cell line models have been used to develop gene expression signatures unique to cancer cells that have metastasized to specific organs, although these efforts were not in a uniform setting. In this study, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung metastasis (LMD-231), bone metastasis (BMD-231), adrenal metastasis (ADMD-231) and brain metastasis (231-BR) variants grown under the same growth condition. When gene expression differences between metasteses (p value of <0.01) were compared, 231-BR cells showed the highest gene expression difference (633 genes) followed by ADMD-231 (196 genes), LMD-231 (79 genes), and BMD-231 cells (60 genes) compared with other metastatic cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 by more than five fold compared with cells isolated from other sites of metastasis. Ingenuity pathway analysis of differentially expressed genes revealed activation of pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.To test this possibility, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. Between metastatic cells, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1. pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231. Cells were maintained in MEM with 10% fetal calf serum. RNA was prepared exponentially growing cells using RNeasy kit (Qiagen, Valencia, CA, USA) Microarray with biological triplicates was performed using Illumina HumanHT-12 V4 expression beadchip. Probe profile data was imported into partek genomics suite. Genes that showed statistically insignificant signals in majority of samples were removed from the microarray data, and only those probes that showed statistically significant signal in at least half of samples of at least one group were retained. Differential expression analysis was performed using ANOVA.

Project description:Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3), and cell anchorage related proteins (MCAM, and SUSD5), some of which were basally modulated by TGFbeta in tumor cells and in conditions mimicking tumor-stroma interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGFbeta blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone-matrix degradation by a dual mechanism of induction of TGFbeta-dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell-autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization. Experiment Overall Design: Human highly metastatic cell lines derived from Non-Small Cell Lung Carcinoma (NSCLC) with specific bone tropism. Cell lines were selected by induction of prominent bone metastases lesions. The metastatic lines were systematically and accurately discriminate using 3 complementary parameters: survival curves of newly injected mice; computerized image analysis of bone metastatic areas; conspicuous SCCs derived from each animal (10 mice/group). Experiment Overall Design: Genome-wide expression analysis was done using 13 microarrays, corresponding to 4 samples of control non-metastatic cell lines and 9 samples of 3 different highly metastatic cell lines (M1, M4, M5) each with 3 biological replicates. Moreover, in each microarray pools of 3 groups of the corresponding cells were used.

Project description:Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtypes. Various cell line models have been used to develop gene expression signatures unique to cancer cells that have metastasized to specific organs, although these efforts were not in a uniform setting. In this study, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung metastasis (LMD-231), bone metastasis (BMD-231), adrenal metastasis (ADMD-231) and brain metastasis (231-BR) variants grown under the same growth condition. When gene expression differences between metasteses (p value of <0.01) were compared, 231-BR cells showed the highest gene expression difference (633 genes) followed by ADMD-231 (196 genes), LMD-231 (79 genes), and BMD-231 cells (60 genes) compared with other metastatic cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 by more than five fold compared with cells isolated from other sites of metastasis. Ingenuity pathway analysis of differentially expressed genes revealed activation of pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.To test this possibility, we compared gene expression pattern in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. Between metastatic cells, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. 231-BR cells specifically overexpressed neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1. pathways that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR cells, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all metastatic cells except BMD-231.

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Early urine proteome changes in an implanted bone cancer rat model

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Early urine proteome changes in an implanted bone cancer rat model.

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