Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts.
The interactions between cancer cells and surrounding stroma play a critical role in tumor progression, but their molecular basis is largely unknown. Global gene expression profiling was performed using oligonucleotide microarrays to determine changes in the gene expression of pancreatic cancer cells (CFPAC1) and stromal fibroblasts induced by coculture. This analysis identified multiple genes as differentially expressed in pancreatic cancer cells and in fibroblasts as a consequence of their mutual interactions, including those that encode for proteins associated with tumor invasion, metastasis, and angiogenesis. Among the genes identified, the cyclooxygenase-2 (COX-2)/PTGS2 gene was of particular interest because COX-2 expression was markedly augmented in both cell types (cancer cells and fibroblasts) in response to coculture. Coculture with fibroblasts also induced COX-2 expression in additional pancreatic cancer cells with an unmethylated COX-2 promoter, but not in those with a methylated COX-2 promoter. Using an in vitro invasion assay, we found an increase in the invasive potential of CFPAC1 cells when they were cocultured with fibroblasts, an effect blocked partially by the addition of a selective COX-2 inhibitor, NS-398, or by COX-2 knockdown with small interfering RNA. Thus, COX-2 inhibitors can decrease the invasive properties of pancreatic cancer cells acquired through tumor-stromal interactions.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Norihiro
N
Sato
Naoki
N
Maehara
Michael
M
Goggins
D002450:Cell Communication / Q000235:genetics*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology; D014162:Transfection; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases