Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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System-Wide Analysis Reveals a Complex Network of Tumor-Fibroblast Interactions Involved in Tumorigenicity

ABSTRACT: Weâve undertaken a genome-wide approach to identify and test genes in fibroblasts that are both induced upon interaction with basal breast cancer cells in culture and upregulated in stromal cells from primary human breast cancers. Several of the upregulated genes encode secreted growth factors or cytokines. Using RNAi and a co-injection tumorigenicity assay, we determined that the majority of secreted factors selected for functional validation played significant, yet functionally diverse, roles in promoting tumorigenicity. Rather than a single major mediator, these results indicate multiple points of intervention to prevent fibroblasts from supporting basal breast cancer. Additionally, we show that breast cancer subtypes differ markedly in the expression of these and other stromally secreted proteins using data from microdissected stromal samples. Induction of genes in four different fibroblast strains (HFFF2, HFF1, CCD1112Sk and Wi38) upon coculture with Cal51 and MDAMB231 human basal breast cancer cell lines. Monocultures of each group are used as the experimental control with each group having 3-4 independent biological replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Jinyu Li

PROVIDER: E-GEOD-41678 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.

Rajaram Megha M Li Jinyu J Egeblad Mikala M Powers R Scott RS

PLoS genetics 20130919 9

Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose ...[more]

PMID: 24068959

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Project description:Spontaneous metastasis of gastric carcinoma to secondary organs is seldom reproduced in the mice. In this study, we established highly reproducible, experimental mice model in which gastric carcinoma progressively grows in the site of gastric walls and metastasize to secondary sites. A highly tumorigenic GC cells were engineered to express type 2 luciferase and injected via orthotopic route into BALB/c nude mice. The mice developed highly progressive GC tumors in the gastric wall where implanted and slow metastases to liver, spleen, lung, kidney and ovary, with rate of metastases to ovary being 63.6% of implanted mice. The tumors colonized in the ovary expressed a GI marker MUC5A, suggestive of typical human Krukenberg tumor. Immuno-histochemical stainings revealed that many mesenchymal markers were strongly positive in motile tumor cells in the vein of ovary and became gradually weak during extravasations to colonize in the ovary. When routes of metastasis were further investigated, the mesenchymal marker SMA stained low in the tumor cells of the primary site of stomach wall, became high in intravasating vein in the stomach wall, remained high in extravasating veins in the liver and ovary and finally returned low in the colonized tumor in the liver and ovary. However, expression of an epithelial marker Claudin did not show in the opposite profile to SMA, indicating that acquisition of mesenchymal phenotypes rather than loss of epithelial characteristics may more give rise to metastatic potential. Dissociated cells derived from tumors in the implanted mouse stomach or metastasized to ovaries retain their tumorigenicity and metastatic potentials. The mRNA microarray and Western blot analyses showed that metastatic tumor-derived cells showed significantly higher expression of GAGE12 gene family than orthotopic tumors-derived cells. The shRNA-mediated knock-down of the GAGE12 family in the metastatic tumors-derived cells abolished the tumor formation in gastric wall and metastasis as well. In conclusion, we established an in vivo orthotopic gastric cancer mouse model spontaneously metastasizing to secondary organs including ovary, which exhibits typical characteristics of a Krukenberg tumor. Expression of mesenchymal markers should be functionally associated with the gain of metastatic ability in this study. A hightly tumorigenic gastric carcinoma SNU-16 cells were orthotpically injected into stomach wall. Tumors formed in the stomach wall (16S) and mestasized to ovary (16O) were dissociated and cultured for 7 day. These cells were re-injected orthotopically and tumors formed in the stomach from 16S (16SS) and ovary from 16O injection (16OO) were dissociated. Total RNAs were isolated from 16S, 16SS, 16O and 16OO2 and subjected to mRNA microarrays

Dataset Information

System-Wide Analysis Reveals a Complex Network of Tumor-Fibroblast Interactions Involved in Tumorigenicity

Publications

System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.

Similar Datasets

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