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Articles by C. J Creighton
Total Records ( 3 ) for C. J Creighton
  O Dakhova , M Ozen , C. J Creighton , R Li , G Ayala , D Rowley and M. Ittmann
 

Purpose: Marked reactive stroma formation, designated as grade 3 reactive stroma, is associated with poor outcome in clinically localized prostate cancer. To understand the biological processes and signaling mechanisms underlying the formation of such reactive stroma, we carried out microarray gene expression analysis of laser-captured reactive stroma and matched normal stroma.

Experimental Design: Seventeen cases of reactive stroma grade 3 cancer were used to laser-capture tumor and normal stroma. Expression analysis was carried out using Agilent 44K arrays. Up-regulation of selected genes was confirmed by quantitative reverse transcription-PCR. Expression data was analyzed to identify significantly up- and down-regulated genes, and gene ontology analysis was used to define pathways altered in reactive stroma.

Results: A total of 544 unique genes were significantly higher in the reactive stroma and 606 unique genes were lower. Gene ontology analysis revealed significant alterations in a number of novel processes in prostate cancer reactive stroma, including neurogenesis, axonogenesis, and the DNA damage/repair pathways, as well as evidence of increases in stem cells in prostate cancer reactive stroma.

Conclusions: Formation of reactive stroma in prostate cancer is a dynamic process characterized by significant alterations in growth factor and signal transduction pathways and formation of new structures, including nerves and axons.

  D. L Gibbons , W Lin , C. J Creighton , Z. H Rizvi , P. A Gregory , G. J Goodall , N Thilaganathan , L Du , Y Zhang , A Pertsemlidis and J. M. Kurie
 

Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-β or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.

  K Choi , Y. H Ahn , D. L Gibbons , H. T Tran , C. J Creighton , L Girard , J. D Minna , F. X. F Qin and J. M. Kurie
 

Notch signaling is activated in a subset of non-small cell lung cancer cells because of overexpression of Notch3, but the role of Notch ligands has not been fully defined. On the basis of gene expression profiling of a panel of non-small cell lung cancer cell lines, we found that the predominant Notch ligands were JAG1, JAG2, DLL1, and DLL3. Given that Notch ligands reportedly have overlapping receptor binding specificities, we postulated that they have redundant biological roles. Arguing against this hypothesis, we found that JAG1 and JAG2 were differentially regulated; JAG1 expression was dependent upon epidermal growth factor receptor (EGFR) activation in HCC827 cells, which require EGFR for survival, whereas JAG2 expression was EGFR-independent in these cells. Furthermore, HCC827 cells underwent apoptosis following depletion of JAG1 but not JAG2, whereas co-culture experiments revealed that depletion of JAG2, but not JAG1, enhanced the ability of HCC827 cells to chemoattract THP-1 human monocytes. JAG2-depleted HCC827 cells expressed high levels of inflammation-related genes, including interleukin 1 (IL1) and a broad range of IL1-regulated cytokines, which was attenuated by inhibition of IL1 receptor (IL1R). Our findings suggest that JAG1 and JAG2 have distinct biological roles including a previously undiscovered role for JAG2 in regulating the expression of cytokines that can promote antitumor immunity.

 
 
 
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