Overexpression of pRB in Human Pancreatic Carcinoma Cells: Function in Chemotherapy-Induced Apoptosis

Plath, T.; Peters, Michael; Detjen, Katharina; Welzel, Martina; Marschall, Zofia von; Radke, Cornelia; Wiedenmann, Bertram; Rosewicz, Stefan

doi:10.1093/jnci/94.2.129

Cited by 34 publications

(30 citation statements)

References 45 publications

(64 reference statements)

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“…Also consistent with PTEN suppression, after TLR7 ligation, we found elevated TGF-β, which is associated with enhanced invasiveness of pancreatic cancer (16). Notably, p16 loss is associated with PanIN lesions at greatest risk for malignant transformation (32,33). The p16 protein transcriptionally inhibited the Rb tumor suppressor.…”

Section: Figuresupporting

confidence: 73%

“…Accordingly, we found marked Rb overexpression in ssRNA40-treated p48Cre;Kras G12D mice. Rb overexpression has also been demonstrated in human pancreatic ductal adenocarcinomas (32). However, our finding was surprising in light of a recent report showing that deletion of Rb accelerates pancreatic carcinogenesis and impairs senescence in premalignant lesions (34).…”

Section: Figurecontrasting

confidence: 44%

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Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

et al. 2012

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Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.

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Section: Figuresupporting

confidence: 73%

Section: Figurecontrasting

confidence: 44%

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

et al. 2012

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“…It is particularly resistant to currently available forms of chemotherapy and radiation therapy. It is thought that this malignancy is able to evade apoptosis induced by treatment with chemotherapeutic drugs because of overexpression of pRb (26). It seems plausible that the inhibitory effect of pRb overexpression on apoptosis may be mediated by E2F.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation

Xiao¹,

Spencer²,

Clements³

et al. 2003

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

133

145

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The retinoblastoma tumor suppressor protein (pRb) regulates the cell cycle, facilitates differentiation, and restrains apoptosis. Furthermore, dysfunctional pRb is thought to be involved in the development of most human malignancies. Many of the functions of pRb are mediated by its regulation of the E2F transcription factors. To understand the structural basis for this regulation, we have determined the crystal structure of a fragment of E2F in complex with the pocket domain of the tumor suppressor protein.The pRb pocket, comprising the A and B cyclin-like domains, is the major focus of tumourigenic mutations in the protein. The fragment of E2F used in our structural studies, residues 409 -426 of E2F-1, represents the core of the pRb-binding region of the transcription factor. The structure shows that E2F binds at the interface of the A and B domains of the pocket making extensive interactions with conserved residues from both. We show by solution studies that a second site, probably contained within the ''marked box'' region of E2F, is responsible for additional interactions with the pRb pocket but is insufficient for complex formation on its own. In addition, we show that the interaction of the core binding fragment of E2F with pRb is inhibited by phosphorylation of the tumor suppressor protein by CDK2͞cyclin D͞E. Finally, our data reveal that the tight binding of the human papillomavirus E7 oncoprotein to pRb prevents subsequent interactions with the marked box region of E2F but not with its core binding region.

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“…The human pancreatic carcinoma cell lines MiaPaca (American Type Culture Collection), DanG, and the murine lymphoma cell line YAC-1 (DSMZ) were cultured as described previously (16,17). MiaPaca cells, stably transfected with an angiopoetin-2 DNA construct, were maintained as MiaPaca wild-type cells, except for the addition of hygromycin B (400 Ag/mL; Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

Wagner

Schulz

Scholz

et al. 2008

Clinical Cancer Research

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Purpose: Effective control of pancreatic cancer has been hampered primarily by the lack of tumor specificity of current treatment modalities. The highly specific antibody-mediated delivery of therapeutic agents to the tumor microenvironment might overcome this problem. We therefore investigated the therapeutic efficacy of the targeted immunocytokine L19-Interleukin-2 (L19-IL2), consisting of the human single-chain Fv antibody L19, which is highly specific for the extradomain B (ED-B) of fibronectin, and the human cytokine IL-2, in pancreatic cancer. Experimental Design: Therapeutic effects of L19-IL-2, IL-2, and gemcitabine on tumor growth and metastasis were evaluated in orthotopic mouse models for pancreatic cancer. Immunohistochemistry was done to define ED-B expression, tumor necrosis, apoptosis, proliferation, and invasion of macrophages and natural killer (NK) cells. NK cells were depleted by i.v. injection of an anti-asialo-GM-1antibody. Results: ED-B is selectively expressed in human pancreatic cancer and in primary tumors and metastases of the mouse models. L19-IL-2 therapy was clearly superior to untargeted IL-2 or gemcitabine and inhibited tumor growth and metastasis with remarkable long-term tumor control. Therapeutic effects were associated with the induction of extensive tumor necrosis and inhibition of tumor cell proliferation. Immunohistochemistry revealed an increase of macrophages and NK cells in the tumor tissue, suggesting immune-mediated mechanisms. The functional relevance of NK cells for the therapeutic effect of the targeted immunocytokine L19-IL-2 was confirmed by NK cell depletion, which completely abolished its antitumor efficacy. Conclusions: These preclinical results strongly encourage the initiation of clinical studies using L19-IL-2 in pancreatic cancer.

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Overexpression of pRB in Human Pancreatic Carcinoma Cells: Function in Chemotherapy-Induced Apoptosis

Abstract: Overexpression of pRB is associated with human pancreatic duct-cell cancer and may allow pancreatic cancer cells to evade chemotherapy-induced apoptosis.

Cited by 34 publications

References 45 publications

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

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