Computational dissection of tissue contamination for identification of colon cancer‐specific expression profiles

Türeci, Özlem; Ding, Jun; Hilton, Holly; Bian, Hongjin; Ohkawa, Hitomi; Braxenthaler, Michael; Seitz, Gerhard; Raddrizzani, Laura; Friess, Helmut; Büchler, Markus W.; Şahin, Uğur; Hammer, Juergen

doi:10.1096/fj.02-0478com

Cited by 39 publications

(22 citation statements)

References 30 publications

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“…[10][11][12][13][14][15][16][17][18][19][20][21] However, few studies have directly addressed the mechanisms of metastasis formation or sup-FIGURE 2 -Confirmation of microarray data by RT-PCR on 6 RNAs from each group of tumors; 100 ng of each linearly amplified RNA were reversely transcribed and used as PCR templates. While b-actin was expressed at comparable levels in all groups of tumors, GnT-IV and Nup50 were dramatically upregulated in the metastasizing primary tumors and in the correspondent metastases.…”

Section: Discussionmentioning

confidence: 99%

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

D’Arrigo

Belluco

Ambrosi

et al. 2005

Intl Journal of Cancer

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Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (a-1,3-)-glycoprotein b-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications. ' 2005 Wiley-Liss, Inc.Key words: DNA microarray; metastasis; colorectal cancer Colorectal carcinoma (CRC) is the second leading cause of cancer deaths in developed countries.1 Metastatic spread, mostly to the liver, is the major cause of mortality in patients with this disease. Yet while the molecular events involved in the CRC adenoma-carcinoma sequence have been largely characterized, 2 little information is available on the mechanisms responsible for the metastatic phenotype. The identification in the primary tumors of molecular factors predictive of metastatic risk may have a relevant clinical impact, allowing for more personalized and effective treatment of CRC patients.Recent evidence based on gene expression profiling has shown that a metastatic fingerprint is detectable in the bulk of primary lung and breast tumors.3,4 On the other hand, no such metastatic signature has been demonstrated in CRC. A general problem related to gene expression studies in the oncologic field is the heterogeneous histology of the bioptic specimens that may contain, in addition to cancer cells, significant fractions of nonneoplastic tissue. Due to this heterogeneity, relevant changes in cancer cell gene expression may be easily overlooked.In order to seek for gene expression patterns specific to metastasis in CRC carcinoma, avoiding interference from nontumoral tissue, we combined laser microdissection of cancer cells and DNA microarray to compare the transcriptional profile of primary colon carcinomas both with that of patient-matched liver metastases and with that of a group of primary tumors of meta...

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Section: Discussionmentioning

confidence: 99%

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

D’Arrigo

Belluco

Ambrosi

et al. 2005

Intl Journal of Cancer

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“…Thus, the findings of robust apolipoprotein gene by expression profiling may reflect the presence of tumor-promoting macrophages within the host stromal response to these primary neoplasms as well. [30][31][32][33][34] While numerous investigations have focused on tumor-stromal interactions at the site of primary invasion, few have addressed these interactions in relation to the primary versus secondary sites of growth. [35][36][37][38][39][40] Our preliminary data of the host response in matched primary and metastatic disease suggests that the host stromal response generated to an infiltrating carcinoma may relate, in part, to the primary versus secondary organ microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Stromal responses to carcinomas of the pancreas: Juxtatumoral gene expression conforms to the infiltrating pattern and not the biologic subtype

Ricci¹,

Kern²,

Hruban³

et al. 2005

Cancer Biology & Therapy

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If there is a "science" of tumor-stromal interactions, there must be a set of biologic rules that are organ-site dependent. One way to explore this hypothesis would be to compare the patterns of gene expression of two biologically distinct neoplasms that arise within the same organ site. Using nonradioactive in situ hybridization, we evaluated the gene expression patterns of three genes previously shown to be robust markers of the juxtatumoral stroma within eight infiltrating ductal adenocarcinoma of the pancreas (ApoC1, ApoD and MMP11), and compared these patterns to those associated with seven infiltrating colloid and tubular carcinomas arising in association with intraductal papillary mucinous neoplasms (IPMNs), a histologically distinct form of primary carcinoma of the pancreas, two surgically resected samples of chronic pancreatitis and two surgically resected pancreatic cancer liver metastases. Robust juxtatumoral stromal expression was noted for all three markers within all eight conventional infiltrating ductal adenocarcinoma tissues, but not in samples of chronic pancreatitis. Among the carcinomas arising within an IPMN, expression for all three markers was also noted for five of seven infiltrating carcinomas analyzed. However, when labeling for these three markers was analyzed with respect to infiltrative growth pattern, positive labeling was only seen in areas of tubular (ductal-type) growth and not in areas of colloid carcinoma. This observation was further supported by two infiltrating carcinomas arising in an IPMN that showed both tubular and colloid growth patterns within the same neoplasm indicating the host stromal response observed may relate to infiltrative growth pattern rather than the biology of the primary tumor type. Moreover, these robust patterns within conventional infiltrating ductal adenocarcinomas were not retained within matched metastases to the liver, indicating the importance of the tumor microenvironment in the host stromal response. Juxtatumoral stroma was found to be composed of a least two cell types, tumor-infiltrating macrophages and fibroblasts, highlighting the complexity of tumor-stromal interactions within an infiltrating carcinoma. Since the juxtatumoral gene expression response is the strongest indication of direct communication between stroma and cancer cells, we provide evidence of a stereotypical response to infiltrative growth that might predominate in tumor-stromal interactions independent of cancer type, a finding with clinical implications for therapeutic modalities that target this response in human tumors.

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“…It contains about 10 000 full-length human genes from the UniGene database (Build 95). Poly (A) þ RNA isolation, cDNA synthesis and cRNA in vitro transcription was carried out as reported previously Tureci et al, 2003). The in vitro transcription product was purified and fragmented as described Tureci et al, 2003).…”

Section: Cdna Arraymentioning

confidence: 99%

“…Poly (A) þ RNA isolation, cDNA synthesis and cRNA in vitro transcription was carried out as reported previously Tureci et al, 2003). The in vitro transcription product was purified and fragmented as described Tureci et al, 2003). Hybridization of the fragmented in vitro transcription product to oligonucleotide arrays was performed as suggested by the manufacturer (Affymetrix Inc.).…”

Section: Cdna Arraymentioning

confidence: 99%

Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma

Guo

Kleeff

et al. 2004

Oncogene

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6716.3%) and metastatic tissues (71.773.1%) compared to normal samples (8.371.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.

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Computational dissection of tissue contamination for identification of colon cancer‐specific expression profiles

Cited by 39 publications

References 30 publications

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

Stromal responses to carcinomas of the pancreas: Juxtatumoral gene expression conforms to the infiltrating pattern and not the biologic subtype

Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma

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