Gene Expression Profiling of Tumor–Stromal Interactions between Pancreatic Cancer Cells and Stromal Fibroblasts

Sato, Norihiro; Maehara, Naoki; Goggins, Michael

doi:10.1158/0008-5472.can-04-0677

Cited by 143 publications

(119 citation statements)

References 34 publications

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“…1A). This observation was consistent with findings in pancreatic cancer, where COX-2 expression was markedly augmented in tumor cells in response to coculture with fibroblasts, and down-regulation of COX-2 decreased the invasive properties of cancer cells acquired through epithelial-mesenchymal interactions (17). However, in contrast to this in vitro pancreatic cancer study, we did not see up-regulation of COX-2 in the stromal cells of any of the xenografts (Fig.…”

Section: Resultssupporting

confidence: 92%

Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Peluffo²,

Chen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

152

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Epithelial-stromal cell interactions have an important role in breast tumor progression, but the molecular mechanisms underlying these effects are just beginning to be understood. We previously described that fibroblasts promote, whereas normal myoepithelial cells inhibit, the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinomas by using a xenograft model of human DCIS. Here, we report that the tumor growth and progression-promoting effects of fibroblasts are at least in part due to increased COX-2 expression in tumor epithelial cells provoked by their interaction with fibroblasts. Up-regulation of COX-2 in DCIS xenografts resulted in increased VEGF and MMP14 expression, which may contribute to the larger weight and invasive histology of COX-2-expressing tumors. Administration of celecoxib, a selective COX-2 inhibitor, to tumor-bearing mice decreased xenograft tumor weight and inhibited progression to invasion. Coculture of fibroblasts with DCIS epithelial cells enhanced their motility and invasion, and this change was associated with increased MMP14 expression and MMP9 protease activity. We identified the NF-B pathway as one of the mediators of stromal fibroblast-derived signals regulating COX-2 expression in tumor epithelial cells. Inhibition of NF-B and COX-2 activity and down-regulation of MMP9 expression attenuated the invasion-promoting effects of fibroblasts. These findings support a role for COX-2 in promoting the progression of DCIS to invasive breast carcinomas, and suggest that therapeutic targeting of the NF-B and prostaglandin signaling pathways might be used for the treatment and prevention of breast cancer.breast cancer ͉ stroma ͉ tumor progression ͉ DCIS ͉ celecoxib

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Section: Resultssupporting

confidence: 92%

Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Peluffo²,

Chen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

152

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“…D2-40 reactivity is also observed in myofibroblasts of the prostate, and myoepithelial cells of breast 49,50 Thus, cancer-associated fibroblasts contribute to cancer growth and metastatic progression, and are expected to the drug targets for anticancer therapy. 51 Podoplanin has not previously been linked to tumor-associated stroma; however, intratumoral D2-40-positive myofibroblasts may play a role in tumor progression due to the close interaction of cancer cells and D2-40-positive myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

et al. 2008

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Lymph node metastasis via lymphatic vessels is related with an adverse outcome in many tumors. It is unclear whether lymphatic spread needs the development of the new lymphatic vessels or the expression of lymphangiogenetic factor in intrahepatic cholangiocarcinoma. The aim of this study was to assess the role of lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression, and D2-40-positive myofibroblastic cells for lymphatic spread and patient outcome in 88 cases of intrahepatic cholangiocarcinoma. We also assessed VEGF-C expression in 15 cases of metastatic lymph nodes. There was a significant correlation between lower lymphatic vessel density in the tumor center and positive lymphatic invasion (P ¼ 0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P ¼ 0.0315 and P ¼ 0.0360, respectively). Lymphatic invasion was observed higher in the peritumoral area (63%, 24/38) and in the tumor periphery (79%, 30/38) than in the tumor center (27%, 9/ 38). There was no significant correlation between the proliferative lymphatic vessels and pathologic features; however, lymphatic invasion was significantly associated with VEGF-C expression (P ¼ 0.0006), and the VEGF-C expression was seen in 12 of 15 cases (80%) of metastatic lymph node. Nodal metastasis was correlated with D2-40-positive myofibroblasts (P ¼ 0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P ¼ 0.0131). Our findings suggest that VEGF-C has an important role in lymphatic invasion via the preexisting lymphatic vessels in the tumor margin, and that lymphangiogenesis does not play a direct role in lymphatic metastasis. D2-40-positive myofibroblasts may contribute to lymphatic metastasis.

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“…In addition to growth factors and pro-angiogenic factors, CAFs secrete ECM remodeling factors, including collagen type I & IV, secreted protein acidic and rich in cysteine (SPARC) and MMPs [99,100]. Secretion of these factors by CAFs is likely induced by the signals derived from the tumor cells or other stromal components and can lead to development of an invasive phenotype [12].…”

Section: Inflammation In the Tme Drives Invasionmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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Gene Expression Profiling of Tumor–Stromal Interactions between Pancreatic Cancer Cells and Stromal Fibroblasts

Cited by 143 publications

References 34 publications

Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

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