Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to ApcMin/+ tumorigenesis

Markova, Marina; Koratkar, Revati; Silverman, Karen A.; Sollars, Vincent E.; MacPhee-Pellini, Melina; Walters, Robin G.; Palazzo, Juan; Buchberg, Arthur M.; Siracusa, Linda D.; Farber, Steven A.

doi:10.1038/sj.onc.1208791

Cited by 19 publications

(18 citation statements)

References 34 publications

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“…Notably, the C3H/He mouse strain has the tumorresistant Pla2g2a allele ( Figure 1C) (Markova et al 2005). Taken together, our results in Apc 1322T mice and reported data in Apc Min and Apc D242 mice (Dietrich et al 1993;Crist et al 2010) indicate that Pla2g2a polymorphisms can affect intestinal tumorigenesis in Apc-mutant mice, independent of the nature of Apc mutation.…”

Section: Discussionsupporting

confidence: 73%

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

et al. 2014

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Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies.

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Section: Discussionsupporting

confidence: 73%

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

et al. 2014

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“…Genetic and transgenic studies suggest that at least one component of the Mom1 locus is the secretory phospholipase A 2 group IIA gene (Pla2g2a) (7,8,36). All Mom1 S strains tested to date have a single base pair insertion in Pla2g2a resulting in the absence of detectable Pla2g2a message and sPLA 2 -IIA activity, whereas all Mom1 R strains, including BALB/c, have a wild-type Pla2g2a allele and high levels of sPLA 2 -IIA activity (19,27,36,37). How the sPLA 2 -IIA protein confers tumor resistance remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c- Rag2 ^−/− Apc ^{Min
/+} Mouse

Nagamine¹,

Sohn

Rickman³

et al. 2008

Infect Immun

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؊/؊ Apc Min/؉ ) was generated. BALB-RagMin mice had a significant increase in tumors in the small, but not large, intestine relative to their BALB-Min counterparts (43.0 versus 24.0 tumors/mouse, respectively). The results suggest that the adaptive immune system plays a role in either the elimination or the equilibrium phase of cancer immunoediting in the small intestine in this model. We investigated the effect of the enterohepatic bacterial pathogen Helicobacter hepaticus on liver and intestine tumorigenesis in BALB-RagMin mice. H. hepaticus-infected BALB-RagMin mice developed moderate hepatitis, moderate typhlitis, and mild colitis. There were no differences in small intestine and cecal tumor multiplicity, regionality, or size relative to that in uninfected mice. However, H. hepaticus-infected BALB-RagMin mice had a significant increase in colon tumor incidence relative to uninfected BALB-RagMin mice (23.5% versus 1.7%, respectively). The data suggest that H. hepaticus, which is present in many research colonies, promotes colon tumorigenesis in the BALB-RagMin mouse and that it has the potential to confound colon tumorigenesis studies.

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“…The following recombinant human sPLA 2 isoforms were prepared as described previously: hGIIA (27,28), hGV (29), and hGX (19). The hGV enzyme was generously provided by Dr. Wonhwa Cho (University of Illinois, Chicago).…”

Section: Methodsmentioning

confidence: 99%

Kinetic Evaluation of Cell Membrane Hydrolysis during Apoptosis by Human Isoforms of Secretory Phospholipase A2

Olson

Nelson

Griffith

et al. 2010

Journal of Biological Chemistry

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Some isoforms of secretory phospholipase A 2 (sPLA 2 ) distinguish between healthy and damaged or apoptotic cells. This distinction reflects differences in membrane physical properties. Because various sPLA 2 isoforms respond differently to properties of artificial membranes such as surface charge, they should also behave differently as these properties evolve during a dynamic physiological process such as apoptosis. To test this idea, S49 lymphoma cell death was induced by glucocorticoid (6 -48 h) or calcium ionophore. Rates of membrane hydrolysis catalyzed by various concentrations of snake venom and human groups IIa, V, and X sPLA 2 were compared after each treatment condition. The data were analyzed using a model that evaluates the adsorption of enzyme to the membrane surface and subsequent binding of substrate to the active site. Results were compared temporally to changes in membrane biophysics and composition. Under control conditions, membrane hydrolysis was confined to the few unhealthy cells present in each sample. Increased hydrolysis during apoptosis and necrosis appeared to reflect substrate access to adsorbed enzyme for the snake venom and group X isoforms corresponding to weakened lipid-lipid interactions in the membrane. In contrast, apoptosis promoted initial adsorption of human groups V and IIa concurrent with phosphatidylserine exposure on the membrane surface. However, this observation was inadequate to explain the behavior of the groups V and IIa enzymes toward necrotic cells where hydrolysis was reduced or absent. Thus, a combination of changes in cell membrane properties during apoptosis and necrosis capacitates the cell for hydrolysis differently by each isoform.During programmed cell death, or apoptosis, a variety of changes occur in the plasma membrane of the cell. These include morphological alterations that emerge late in the process such as blebbing and increased permeability of the membrane. Earlier in the process, several more subtle membrane changes occur. The best studied is a loss of the normal asymmetrical transmembrane distribution of phospholipid species. Consequently, anionic lipids like phosphatidylserine, which are typically confined to the inner leaflet of the membrane, become exposed on the outer surface (1). In addition, studies with fluorescent membrane probes have revealed possible increases in fluidity and/or the spacing between lipid molecules that may precede or coincide with the loss of membrane asymmetry, depending on the cell type and mode of apoptosis (2-9). Recently, a latent increase in the order of membrane lipids has also been reported (9).A potential consequence of these events during apoptosis is enzymatic attack of the cell membrane by secretory phospholipase A 2 (sPLA 2 ).2 Ordinarily, healthy cells resist hydrolysis, but during apoptosis they become vulnerable to destruction by the enzyme (9 -11). Studies with snake venom phospholipase A 2 have identified possible ways by which this phenomenon relates to membrane physical properties (8,9,12). Prelimina...

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Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to ApcMin/+ tumorigenesis

Cited by 19 publications

References 34 publications

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c- Rag2 ^−/− Apc ^{Min
/+} Mouse

Kinetic Evaluation of Cell Membrane Hydrolysis during Apoptosis by Human Isoforms of Secretory Phospholipase A2

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Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to ApcMin/+ tumorigenesis

Cited by 19 publications

References 34 publications

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c- Rag2 −/− Apc Min /+ Mouse

Kinetic Evaluation of Cell Membrane Hydrolysis during Apoptosis by Human Isoforms of Secretory Phospholipase A2

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Helicobacter hepaticus Infection Promotes Colon Tumorigenesis in the BALB/c- Rag2 ^−/− Apc ^{Min
/+} Mouse