Direct growth suppressive activity of interferon-? and -? on human gastric cancer cells

Shyu, Rong-Yaun; Yu, Jyh-Cheng; Jiang, Shun-Yuan

doi:10.1002/1096-9098(200010)75:2<122::aid-jso9>3.0.co;2-4

Cited by 22 publications

(8 citation statements)

References 30 publications

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“…The question that then arises is how IFN␥ negatively regulates NP proliferation. One possibility is that IFN␥ induces cell-cycle arrest, an action that has been demonstrated previously in carcinoma cells (Burke et al, 1997;Shyu et al, 2000;Vivo et al, 2001;Baka et al, 2009) and mammalian epithelial cells (Harvat and Jetten, 1996). The anti-proliferative action in these cells is mainly regulated via activation of signal transducer and activator of transcription 1 (STAT1) and downregulation of cyclin A and cyclin E expression (Kortylewski et al, 2004).…”

Section: Discussionmentioning

confidence: 66%

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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Although a number of growth factors have been shown to be involved in neurogenesis, the role of inflammatory cytokines remains relatively unexplored in the normal brain. Here we investigated the effect of interferon gamma (IFN␥) in the regulation of neural precursor (NP) activity in both the developing and the adult mouse brain. Exogenous IFN␥ inhibited neurosphere formation from the wild-type neonatal and adult subventricular zone (SVZ). More importantly, however, these effects were mirrored in vivo, with mutant mice lacking endogenous IFN␥ displaying enhanced neurogenesis, as demonstrated by an increase in proliferative bromodeoxyuridinelabeled cells in the SVZ and an increased percentage of newborn neurons in the olfactory bulb. Furthermore, NPs isolated from IFN␥ null mice exhibited an increase in self-renewal ability and in the capacity to produce differentiated neurons and oligodendrocytes. These effects resulted from the direct action of IFN␥ on the NPs, as determined by single-cell assays and the fact that nearly all the neurospheres were derived from cells positive for major histocompatibility complex class I antigen, a downstream marker of IFN␥-mediated activation. Moreover, the inhibitory effect was ameliorated in the presence of SVZ-derived microglia, with their removal resulting in almost complete inhibition of NP proliferation. Interestingly, in contrast to the results obtained in the adult, exogenous IFN␥ treatment stimulated neurosphere formation from the embryonic brain, an effect that was mediated by sonic hedgehog. Together these findings provide the first direct evidence that IFN␥ acts as a regulator of the active NP pool in the non-inflammatory brain.

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Section: Discussionmentioning

confidence: 66%

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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“…7,31,41 IFNg facilitates antigen recognition in surrounding cells by promoting MHC class-I expression 42 and it has been recently described that in several models helps to induce programmed cell death of tumor cell lines. [43][44][45][46] Therefore, IFNg, directly or by indirect mechanisms such as macrophage activation, 41 …”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis

et al. 2003

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Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3a (Ad-CMVIL-12+AdCMVMIP3a) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3a. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNg, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNg.

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“…Interferon-g (IFN-g) is a cytokine with pleiotropic effects on various types of cells (David, 1995;Shyu et al, 2000). Although the mechanisms of pleiotropic effects of IFN-g are not fully understood, one of interest is the interaction with TGF-b signals (Ulloa et al, 1999;Gurujeyalakshmi et al, 1995;Tredget et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model

et al. 2003

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We reconstituted a three-dimensional gastric carcinoma model similar to invasive gastric carcinoma tissue. This model consists of a human gastric carcinoma cell line, GCTM-1, a human fibroblast cell line, TIG-1-20, and transforming growth factor-b (TGF-b)-containing type I collagen gel. Using this model, we were able to observe the growth of the two cell types, especially carcinoma cell invasive growth, in real time for more than 30 days. TGFb and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-b induced the enhanced expression of matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) in GCTM-1 at both the protein and enzymatic activity levels. The TGF-b-induced invasion of GCTM-1 was inhibited by MMP9-or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-c (IFN-c) was added to this model, TGF-bdependent GCTM-1 invasion was significantly inhibited, concomitant with the decreased expression of MMP9 and uPA. The intracellular signal transduction of Smad was examined to analyse the mechanism of the inhibitory effect of IFN-c. TGF-b accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3-Smad4 complex in GCTM-1, but these TGF-b-induced effects were significantly inhibited by IFN-c-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGFb-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-c on TGF-b-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-c inhibits TGF-b-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-c may be a new therapeutic tool for TGF-b-expressed invasive carcinomas.

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Direct growth suppressive activity of interferon-? and -? on human gastric cancer cells

Cited by 22 publications

References 30 publications

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis

Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model

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