Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Zucchi, Ileana; Mento, E.; Kuznetsov, Vladimir A.; Scotti, Maddalena; Valsecchi, Valentina; Simionati, Barbara; Vicinanza, E.; Valle, Giorgio; Pilotti, Silvana; Reinbold, Rolland; Vezzoni, Paolo; Albertini, Alberto; Dulbecco, Renato

doi:10.1073/pnas.0408260101

Cited by 98 publications

(72 citation statements)

References 41 publications

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“…Remarkably, we could find less upregulated genes in the liver metastases than in the primary tumour, indicating a possible loss of regulating and tumour suppressor genes. The same observation has been made by other groups Zucchi et al, 2004). Zucchi et al (2004) hypothesised that the downregulation of a set of genes may be the basic mechanism of cancer formation, whereas the upregulation may characterise and possibly control the state of evolution of individual cancers.…”

Section: Discussionsupporting

confidence: 48%

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

et al. 2007

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The prognosis of pancreatic adenocarcinoma is affected by early metastases and local tumour invasion beyond surgical margins. Gene expression profiling in pancreatic cancer tissue is complicated due to the high amount of RNAses being present in human tissue and that of suitable models. In order to demonstrate early metastases, the models should take into account the anatomical environment of the tumour. Using the orthotopic transplantation of pancreatic tumour cells in SCID (severe combined immunodeficiency) mice, these interactions are taken into consideration. In order to identify genes associated with local tumour invasion and metastases in ductal pancreatic cancer, we investigated a human pancreatic tumour cell line derived from an orthopic pancreatic tumour model in SCID mice. Differential gene expression was performed on the basis of microarray technique. The human MiaPaca-2 cell line was implanted orthotopically in SCID mice. Transcriptional profiling was performed on fresh frozen tissue derived from the primary tumour, the tumour invasion front and the liver metastases. Differentially expressed genes were identified using statistical analyses, and were validated with external databases and with immunohistochemistry. A total of 1066 of 14 500 genes were significantly differentially expressed. Comparing the primary tumour with the tumour invasion front, there were 614 statistically significant up-and 348 downregulated genes. Twenty-five statistically significant up-and 181 downregulated genes were identified comparing the liver metastases with the primary tumour. Eight genes (PAI-1, BNIP3l, VEGF, NSE, RGS4, HSP27, GADD45A, PTPN14) were chosen and validated in a semi-quantitative immunohistochemical analysis, which revealed a positive correlation to the array data. Overrepresentation analyses revealed a total of 66 significantly regulated pathways associated with cell proliferation, cell stress, cell communication metabolic and cytokine function. In conclusion, model marker genes for local invasion and liver metastases can be identified using transcriptional profiling in the SCID mouse. Overrepresentation analysis secures a good and fast overview about the significantly regulated genes and can assign genes to certain pathways. These marker genes can be related to the apoptotic cascade, angiogenesis and cell interaction.

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Section: Discussionsupporting

confidence: 48%

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

et al. 2007

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“…Our detection of ODAM in other epithelial malignancies, for example, breast, lung, and gastric cancers, also suggests that this protein is up-regulated in these cancers. Interestingly, the FDC-SP gene, adjacent to ODAM in the SCPP cluster, is expressed in late dental development, as well as in neoplasms of the breast; further, it has been included as a gene signature screening component indicative of breast cancer invasiveness (19,34,35). In the case of colon cancer, this neoplasm results from a progressive series of steps whereby epithelial dysplasia evolves into a flat adenoma, carcinoma in situ, and finally, adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Expression of Odontogenic Ameloblast-Associated Protein (ODAM) in Dental and Other Epithelial Neoplasms

Kestler

Foster

Macy

et al. 2008

Mol Med

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We previously have communicated our discovery that the amyloid associated with calcifying epithelial odontogenic tumors is composed of N-terminal fragments of the structurally novel odontogenic ameloblast-associated protein designated ODAM. Subsequently, it was shown by other investigators that ODAM is expressed in rodent enamel organ and is likely involved in dental development. We now report that this molecule also is found in certain human tissues, principally the salivary gland and trachea, as evidenced by RNA array analysis and immunohistochemistry-utilizing antibodies prepared against synthetic ODAM-related peptides and recombinant protein. Notably, these reagents immunostained normal and malignant ameloblasts and other types of human neoplastic cells, including those of gastric, lung, and breast origin where the presence in the latter was confirmed by in situ hybridization using gene-specific molecular probes. Moreover, significant titers of anti-ODAM IgG antibodies were detected in the sera of patients with these malignancies. Our studies have provided the first evidence in humans for the cellular expression of ODAM in normal and diseased states. Based on our findings, we posit that ODAM is a developmental antigen that has an essential role in tooth maturation and in the pathogenesis of certain odontogenic and other epithelial neoplasms; further, we suggest that ODAM may serve as a novel prognostic biomarker, as well as a potential diagnostic and therapeutic target for patients with breast and other epithelial forms of cancer.

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“…Additionally, it has recently been suggested that Emilin2, which encodes the elastin microfibril interfacer 2, is subject to DNA methylation leading to reduced gene expression in human breast cancers, and Emilin2 hypermethylation is associated with poorer clinical outcome, in particular relapse and poor survival (33). Last, elevated expression of Spdya (also known as Spy1), which encodes the speedy homolog A, accelerates tumorigenesis in a mouse model of breast cancer (34) and has also been associated with more aggressive human breast cancers (35). As such, other genes in this locus merit future investigation.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

Chun

Mao

Chiu

et al. 2010

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

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Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.anaplastic lymphoma kinase | cancer modifier genes | malignant progression | pancreas cancer | transgenic mouse C ancer is a complex disease governed by environmental and genetic factors, including genetic mutations and polymorphisms that modulate cancer susceptibility (1). Although many investigations have focused on identifying factors that affect initial tumor development (2, 3), data from both human and mouse studies have demonstrated that genetic polymorphisms can modulate multiple aspects of tumorigenesis, such as tumor progression (4-6) and response to therapy (7).In this study, we investigated the effects of genetic background on tumor progression to an invasive growth state, motivated by a provocative observation that mice carrying the same oncogenic transgene but differing in genetic background developed tumors that were markedly distinctive in their invasiveness. This model, the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis, develops multiple pancreatic neuroendocrine tumors (PNET) in a relatively synchronous and predictable multistage progression pattern by 12-14 wk of age owing to the expression of the SV40 T antigen oncoprotein (Tag) in the pancreatic β cells (8). The tumorigenesis pathway has predominantly been studied in RT2 mice inbred into the C57BL/6 (B6) background, and the PNETs that arise in this genetic context display a spectrum of invasive phenotypes and can be classified as noninvasive islet tumors (IT), focally invasive type-1 carcinomas (IC1), and broadly invasive type-2 carcinomas (IC2) (9). Surprisingly, we observed that when RT2 mice were inbred into a second strain, C3HeB/Fe (C3H), the tumors that arose were predominantly noninvasive, despite being otherwise similar in their tumorigenesis phenotype. The implication that the invasive phenotype was influenced by genetic background prompted our investigation...

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Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Cited by 98 publications

References 41 publications

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

Expression of Odontogenic Ameloblast-Associated Protein (ODAM) in Dental and Other Epithelial Neoplasms

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

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