Publications by authors named "Nicole R Murray"

39 Publications

Protein kinase C and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Cell Rep 2021 Nov;37(8):110054

Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC inhibitor, whereas resistance to a SRC inhibitor is associated with activated PKCι signaling and sensitivity to auranofin. Interestingly, PKCι- and SRC-dependent cells often co-exist in individual GBM tumors, and treatment of GBM-bearing mice with combined auranofin and SRC inhibitor prolongs survival beyond either drug alone. Thus, we identify PKCι and SRC signaling as distinct therapeutic vulnerabilities that are directly translatable into an improved treatment for GBM.
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http://dx.doi.org/10.1016/j.celrep.2021.110054DOI Listing
November 2021

Recurrent copy number gains drive PKCι expression and PKCι-dependent oncogenic signaling in human cancers.

Adv Biol Regul 2020 12 12;78:100754. Epub 2020 Sep 12.

Department of Cancer Cell Biology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. Electronic address:

PRKCI is frequently overexpressed in multiple human cancers, and PKCι expression is often prognostic for poor patient survival, indicating that elevated PKCι broadly plays an oncogenic role in the cancer phenotype. PKCι drives multiple oncogenic signaling pathways involved in transformed growth, and transgenic mouse models have revealed that PKCι is a critical oncogenic driver in both lung and ovarian cancers. We now report that recurrent 3q26 copy number gain (CNG) is the predominant genetic driver of PRKCI mRNA expression in all major human cancer types exhibiting such CNGs. In addition to PRKCI, CNG at 3q26 leads to coordinate CNGs of ECT2 and SOX2, two additional 3q26 genes that collaborate with PRKCI to drive oncogenic signaling and tumor initiation in lung squamous cell carcinoma. Interestingly however, whereas 3q26 CNG is a strong driver of PRKCI mRNA expression across all tumor types examined, it has differential effects on ECT2 and SOX2 mRNA expression. In some tumors types, particularly those with squamous histology, all three 3q26 oncogenes are coordinately overexpressed as a consequence of 3q26 CNG, whereas in other cancers only PRKCI and ECT2 mRNA are coordinately overexpressed. This distinct pattern of expression of 3q26 genes corresponds to differences in genomic signatures reflective of activation of specific PKCι oncogenic signaling pathways. In addition to highly prevalent CNG, some tumor types exhibit monoallelic loss of PRKCI. Interestingly, many tumors harboring monoallelic loss of PRKCI express significantly lower PRKCI mRNA and exhibit evidence of WNT/β-catenin signaling pathway activation, which we previously characterized as a major oncogenic pathway in a newly described, PKCι-independent molecular subtype of lung adenocarcinoma. Finally, we show that CNG-driven activation of PKCι oncogenic signaling predicts poor patient survival in many major cancer types. We conclude that CNG and monoallelic loss are the major determinants of tumor PRKCI mRNA expression across virtually all tumor types, but that tumor-type specific mechanisms determine whether these copy number alterations also drive expression of the collaborating 3q26 oncogenes ECT2 and SOX2, and the oncogenic PKCι signaling pathways activated through the collaborative action of these genes. Our analysis may be useful in identifying tumor-specific predictive biomarkers and effective PKCι-targeted therapeutic strategies in the multitude of human cancers harboring genetic activation of PRKCI.
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http://dx.doi.org/10.1016/j.jbior.2020.100754DOI Listing
December 2020

Protein kinase Cι promotes UBF1-ECT2 binding on ribosomal DNA to drive rRNA synthesis and transformed growth of non-small-cell lung cancer cells.

J Biol Chem 2020 06 29;295(24):8214-8226. Epub 2020 Apr 29.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA

Epithelial cell-transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho GTPases that is overexpressed in many cancers and involved in signal transduction pathways that promote cancer cell proliferation, invasion, and tumorigenesis. Recently, we demonstrated that a significant pool of ECT2 localizes to the nucleolus of non-small-cell lung cancer (NSCLC) cells, where it binds the transcription factor upstream binding factor 1 (UBF1) on the promoter regions of ribosomal DNA (rDNA) and activates rDNA transcription, transformed cell growth, and tumor formation. Here, we investigated the mechanism by which ECT2 engages UBF1 on rDNA promoters. Results from ECT2 mutagenesis indicated that the tandem BRCT domain of ECT2 mediates binding to UBF1. Biochemical and MS-based analyses revealed that protein kinase Cι (PKCι) directly phosphorylates UBF1 at Ser-412, thereby generating a phosphopeptide-binding epitope that binds the ECT2 BRCT domain. Lentiviral shRNA knockdown and reconstitution experiments revealed that both a functional ECT2 BRCT domain and the UBF1 Ser-412 phosphorylation site are required for UBF1-mediated ECT2 recruitment to rDNA, elevated rRNA synthesis, and transformed growth. Our findings provide critical molecular insight into ECT2-mediated regulation of rDNA transcription in cancer cells and offer a rationale for therapeutic targeting of UBF1- and ECT2-stimulated rDNA transcription for the management of NSCLC.
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http://dx.doi.org/10.1074/jbc.RA120.013175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294082PMC
June 2020

Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma.

Cell Rep 2020 01;30(3):771-782.e6

Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL 32224, USA. Electronic address:

Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC.
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http://dx.doi.org/10.1016/j.celrep.2019.12.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238436PMC
January 2020

Oncogenic protein kinase Cι signaling mechanisms in lung cancer: Implications for improved therapeutic strategies.

Adv Biol Regul 2020 01 25;75:100656. Epub 2019 Sep 25.

From the Department of Cancer Cell Biology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. Electronic address:

Protein Kinase Cι (PKCι) is a major oncogene involved in the initiation, maintenance and progression of numerous forms of human cancer. In the lung, PKCι is necessary for the maintenance of the transformed phenotype of the two major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC). In addition, PKCι is necessary for both LADC and LSCC tumorigenesis by establishing and maintaining a highly aggressive stem-like, tumor-initiating cell phenotype. Interestingly however, while PKCι signaling in these two major lung cancer subtypes shares some common elements, it also drives distinct, sub-type specific pathways. Furthermore, recent analysis has revealed both PKCι-dependent and PKCι-independent pathways to LADC development. Herein, we discussion our current knowledge of oncogenic PKCι signaling in LADC and LSCC, and discuss these findings in the context of how they may inform strategies for improved therapeutic intervention in these deadly diseases.
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http://dx.doi.org/10.1016/j.jbior.2019.100656DOI Listing
January 2020

Protein Kinase Cι and Wnt/β-Catenin Signaling: Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma.

Cancer Cell 2019 08 1;36(2):156-167.e7. Epub 2019 Aug 1.

Department of Cancer Biology, Mayo Clinic Florida, 4500 San Pablo Road, Griffin Cancer Research Building, Room 212, Jacksonville, FL 32224, USA. Electronic address:

We report that mouse LSL-Kras;Trp53 (KP)-mediated lung adenocarcinoma (LADC) tumorigenesis can proceed through both PKCι-dependent and PKCι-independent pathways. The predominant pathway involves PKCι-dependent transformation of bronchoalveolar stem cells (BASCs). However, KP mice harboring conditional knock out Prkci alleles (KPI mice) develop LADC tumors through PKCι-independent transformation of Axin2 alveolar type 2 (AT2) stem cells. Transformed growth of KPI, but not KP, tumors is blocked by Wnt pathway inhibition in vitro and in vivo. Furthermore, a KPI-derived genomic signature predicts sensitivity of human LADC cells to Wnt inhibition, and identifies a distinct subset of primary LADC tumors exhibiting a KPI-like genotype. Thus, LADC can develop through both PKCι-dependent and PKCι-independent pathways, resulting in tumors exhibiting distinct oncogenic signaling and pharmacologic vulnerabilities.
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http://dx.doi.org/10.1016/j.ccell.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693680PMC
August 2019

Protein kinase C: A versatile oncogene in the lung.

Mol Cell Oncol 2018 10;5(5):e1190886. Epub 2018 May 10.

Department of Cancer Biology, Mayo Clinic Florida Jacksonville, Florida.

We have recently demonstrated that protein kinase C (PKC) promotes a stem-like, tumor-initiating cell phenotype in -driven lung adenocarcinoma by activating a novel ELF3-NOTCH3 signaling axis. Combined PKC and NOTCH inhibition was identified as a novel strategy for the treatment of -driven lung adenocarcinoma.
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http://dx.doi.org/10.1080/23723556.2016.1190886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154840PMC
May 2018

Oncogenic Ect2 signaling regulates rRNA synthesis in NSCLC.

Small GTPases 2019 09 5;10(5):388-394. Epub 2017 Jul 5.

a Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center , Jacksonville , FL , USA.

The Rho GTPase family members Rac1, Cdc42 and RhoA play key contributory roles in the transformed phenotype of human cancers. Epithelial Cell Transforming Sequence 2 (Ect2), a guanine nucleotide exchange factor (GEF) for these Rho GTPases, has also been implicated in a variety of human cancers. We have shown that Ect2 is frequently overexpressed in both major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), which together make up approximately 70% of all lung cancer diagnoses. Furthermore, we have found that Ect2 is required for multiple aspects of the transformed phenotype of NSCLC cells including transformed growth and invasion and tumorigenesis . More recently, we showed that a major mechanism by which Ect2 drives -mediated LADC transformation is by regulating rRNA (rRNA) synthesis. However, it remains unclear whether Ect2 plays a similar role in ribosome biogenesis in LSCC. Here we demonstrate that Ect2 expression correlates positively with expression of ribosome biogenesis genes and with pre-ribosomal 45S RNA abundance in primary LSCC tumors. Furthermore, we demonstrate that Ect2 functionally regulates rRNA synthesis in LSCC cells. Based on these data, we propose that inhibition of Ect2-mediated nucleolar signaling holds promise as a potential therapeutic strategy for improved treatment of both LADC and LSCC.
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http://dx.doi.org/10.1080/21541248.2017.1335274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748369PMC
September 2019

Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma.

Cancer Cell 2017 02 19;31(2):256-269. Epub 2017 Jan 19.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address:

The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.
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http://dx.doi.org/10.1016/j.ccell.2016.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310966PMC
February 2017

SOX2 Determines Lineage Restriction: Modeling Lung Squamous Cell Carcinoma in the Mouse.

Cancer Cell 2016 10;30(4):505-507

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. Electronic address:

In this issue of Cancer Cell, Ferone et al. demonstrate that SOX2 not only drives lung tumor formation but also restricts tumor lineage to squamous cell carcinoma (LSCC), regardless of cell of origin. This novel LSCC model should facilitate identification of key oncogenic drivers and treatment strategies for this lung cancer subtype.
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http://dx.doi.org/10.1016/j.ccell.2016.09.012DOI Listing
October 2016

Oncogenic PKCι decides tumor-initiating cell fate.

Cell Cycle 2016 09 17;15(18):2383-4. Epub 2016 Jun 17.

a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026803PMC
http://dx.doi.org/10.1080/15384101.2016.1194624DOI Listing
September 2016

Targeting oncogenic protein kinase Cι for treatment of mutant KRAS LADC.

Small GTPases 2017 01 31;8(1):58-64. Epub 2016 May 31.

a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.

Lung cancer is the leading cause of cancer death in the US with ∼124,000 new cases annually, and a 5 y survival rate of ∼16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Cι (PKCι) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCι inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.
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http://dx.doi.org/10.1080/21541248.2016.1194953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331898PMC
January 2017

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.

Cancer Cell 2016 Mar;29(3):367-378

Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. Electronic address:

We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.
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http://dx.doi.org/10.1016/j.ccell.2016.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795153PMC
March 2016

The chromosome 3q26 OncCassette: A multigenic driver of human cancer.

Adv Biol Regul 2016 Jan 23;60:47-63. Epub 2015 Dec 23.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, United States.

Recurrent copy number variations (CNVs) are genetic alterations commonly observed in human tumors. One of the most frequent CNVs in human tumors involves copy number gains (CNGs) at chromosome 3q26, which is estimated to occur in >20% of human tumors. The high prevalence and frequent occurrence of 3q26 CNG suggest that it drives the biology of tumors harboring this genetic alteration. The chromosomal region subject to CNG (the 3q26 amplicon) spans from chromosome 3q26 to q29, a region containing ∼200 protein-encoding genes. The large number of genes within the amplicon makes it difficult to identify relevant oncogenic target(s). Whereas a number of genes in this region have been linked to the transformed phenotype, recent studies indicate a high level of cooperativity among a subset of frequently amplified 3q26 genes. Here we use a novel bioinformatics approach to identify potential driver genes within the recurrent 3q26 amplicon in lung squamous cell carcinoma (LSCC). Our analysis reveals a set of 35 3q26 amplicon genes that are coordinately amplified and overexpressed in human LSCC tumors, and that also map to a major LSCC susceptibility locus identified on mouse chromosome 3 that is syntenic with human chromosome 3q26. Pathway analysis reveals that 21 of these genes exist within a single predicted network module. Four 3q26 genes, SOX2, ECT2, PRKCI and PI3KCA occupy the hub of this network module and serve as nodal genes around which the network is organized. Integration of available genetic, genomic, biochemical and functional data demonstrates that SOX2, ECT2, PRKCI and PIK3CA are cooperating oncogenes that function within an integrated cell signaling network that drives a highly aggressive, stem-like phenotype in LSCC tumors harboring 3q26 amplification. Based on the high level of genomic, genetic, biochemical and functional integration amongst these 4 3q26 nodal genes, we propose that they are the key oncogenic targets of the 3q26 amplicon and together define a "3q26 OncCassette" that mediates 3q26 CNG-driven tumorigenesis. Genomic analysis indicates that the 3q26 OncCassette also operates in other major tumor types that exhibit frequent 3q26 CNGs, including head and neck squamous cell carcinoma (HNSCC), ovarian serous cancer and cervical cancer. Finally, we discuss how the 3q26 OncCassette represents a tractable target for development of novel therapeutic intervention strategies that hold promise for improving treatment of 3q26-driven cancers.
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http://dx.doi.org/10.1016/j.jbior.2015.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729592PMC
January 2016

A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion.

Oncotarget 2015 Jun;6(17):15297-310

Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.

Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558152PMC
http://dx.doi.org/10.18632/oncotarget.3812DOI Listing
June 2015

Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia.

Nat Commun 2015 Feb 20;6:6200. Epub 2015 Feb 20.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.

The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.
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http://dx.doi.org/10.1038/ncomms7200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394184PMC
February 2015

Complex role for the immune system in initiation and progression of pancreatic cancer.

World J Gastroenterol 2014 Aug;20(32):11160-81

Kristin S Inman, Amanda A Francis, Nicole R Murray, Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States.

The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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http://dx.doi.org/10.3748/wjg.v20.i32.11160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145756PMC
August 2014

The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma.

Cancer Cell 2014 Feb;25(2):139-51

Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. Electronic address:

We report that two oncogenes coamplified on chromosome 3q26, PRKCI and SOX2, cooperate to drive a stem-like phenotype in lung squamous cell carcinoma (LSCC). Protein kinase Cι (PKCι) phosphorylates SOX2, a master transcriptional regulator of stemness, and recruits it to the promoter of Hedgehog (Hh) acyltransferase (HHAT) that catalyzes the rate-limiting step in Hh ligand production. PKCι-mediated SOX2 phosphorylation is required for HHAT promoter occupancy, HHAT expression, and maintenance of a stem-like phenotype. Primary LSCC tumors coordinately overexpress PKCι, SOX2, and HHAT and require PKCι-SOX2-HHAT signaling to maintain a stem-like phenotype. Thus, PKCι and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis.
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http://dx.doi.org/10.1016/j.ccr.2014.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949484PMC
February 2014

Protein kinase C zeta regulates human pancreatic cancer cell transformed growth and invasion through a STAT3-dependent mechanism.

PLoS One 2013 28;8(8):e72061. Epub 2013 Aug 28.

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.

Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756013PMC
May 2014

EGF receptor is required for KRAS-induced pancreatic tumorigenesis.

Cancer Cell 2012 Sep;22(3):304-17

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
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http://dx.doi.org/10.1016/j.ccr.2012.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443395PMC
September 2012

Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential.

PLoS One 2012 24;7(4):e35040. Epub 2012 Apr 24.

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.

Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/-) mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335833PMC
August 2012

Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia.

PLoS One 2012 16;7(2):e30509. Epub 2012 Feb 16.

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.

Pancreatic acinar-to-ductal metaplasia (ADM) is associated with an increased risk of pancreatic cancer and is considered a precursor of pancreatic ductal adenocarcinoma. Transgenic expression of transforming growth factor alpha (TGF-α) or K-ras(G12D) in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCι) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCι expression was assessed in a mouse model of K-ras(G12D)-induced pancreatic ADM and pancreatic cancer. The ability of K-ras(G12D) to induce pancreatic ADM in explant culture, and the requirement for PKCι, was investigated. PKCι is elevated in human and mouse pancreatic ADM and intraepithelial neoplastic lesions in vivo. We demonstrate that K-ras(G12D) is sufficient to induce pancreatic ADM in explant culture, exhibiting many of the same morphologic and biochemical alterations observed in TGF-α-induced ADM, including a dependence on Notch activation. PKCι is highly expressed in both TGF-α- and K-ras(G12D)-induced pancreatic ADM and inhibition of PKCι significantly reduces TGF-α- and K-ras(G12D)-mediated ADM. Inhibition of PKCι suppresses K-ras(G12D)-induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-ras(G12D)-mediated ADM in PKCι-depleted cells, implicating a K-ras(G12D)-PKCι-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCι is an early marker of pancreatic neoplasia and suggest that PKCι is a potential downstream target of K-ras(G12D) in pancreatic ductal metaplasia in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281025PMC
August 2012

Matrix metalloproteinase-10 promotes Kras-mediated bronchio-alveolar stem cell expansion and lung cancer formation.

PLoS One 2011 17;6(10):e26439. Epub 2011 Oct 17.

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.

Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10(-/-)) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195727PMC
February 2012

Protein kinase C iota in the intestinal epithelium protects against dextran sodium sulfate-induced colitis.

Inflamm Bowel Dis 2011 Aug 15;17(8):1685-97. Epub 2010 Nov 15.

Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.

Background: The integrity of the intestinal epithelium is critical for the absorption and retention of fluid and nutrients. The intestinal epithelium also provides a barrier between the intestinal bacteria and the body's immune surveillance. Therefore, intestinal epithelial barrier function is critically important, and disruption of the intestinal epithelium results in rapid repair of the damaged area.

Methods: We evaluated the requirement for protein kinase C iota (PKCι) in intestinal epithelial homeostasis and response to epithelial damage using a well-characterized mouse model of colitis. Mice were analyzed for the clinical, histological, and cellular effects of dextran sodium sulfate (DSS) treatment.

Results: Knockout of the mouse PKCι gene (Prkci) in the intestinal epithelium (Prkci KO mice) had no effect on normal colonic homeostasis; however, Prkci KO mice were significantly more sensitive to DSS-induced colitis and death. After withdrawal of DSS, Prkci KO mice exhibited a continued increase in apoptosis, inflammation, and damage to the intestinal microvasculature and a progressive loss of trefoil factor 3 (TFF3) expression, a regulatory peptide important for intestinal wound healing. Knockdown of PKCι expression in HT-29 cells reduced wound healing and TFF3 expression, while addition of exogenous TFF3 restored wound healing in PKCι-depleted cells.

Conclusions: Expression of PKCι in the intestinal epithelium protects against DSS-induced colitis. Our data suggest that PKCι reduces DSS-induced damage by promoting intestinal epithelial wound healing through the control of TFF3 expression.
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http://dx.doi.org/10.1002/ibd.21547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116999PMC
August 2011

Protein kinase Cι expression and oncogenic signaling mechanisms in cancer.

J Cell Physiol 2011 Apr;226(4):879-87

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.

Accumulating evidence demonstrates that PKCι is an oncogene and prognostic marker that is frequently targeted for genetic alteration in many major forms of human cancer. Functional data demonstrate that PKCι is required for the transformed phenotype of lung, pancreatic, ovarian, prostate, colon, and brain cancer cells. Future studies will be required to determine whether PKCι is also an oncogene in the many other cancer types that also overexpress PKCι. Studies of PKCι using genetically defined models of tumorigenesis have revealed a critical role for PKCι in multiple stages of tumorigenesis, including tumor initiation, progression, and metastasis. Recent studies in a genetic model of lung adenocarcinoma suggest a role for PKCι in transformation of lung cancer stem cells. These studies have important implications for the therapeutic use of aurothiomalate (ATM), a highly selective PKCι signaling inhibitor currently undergoing clinical evaluation. Significant progress has been made in determining the molecular mechanisms by which PKCι drives the transformed phenotype, particularly the central role played by the oncogenic PKCι-Par6 complex in transformed growth and invasion, and of several PKCι-dependent survival pathways in chemo-resistance. Future studies will be required to determine the composition and dynamics of the PKCι-Par6 complex, and the mechanisms by which oncogenic signaling through this complex is regulated. Likewise, a better understanding of the critical downstream effectors of PKCι in various human tumor types holds promise for identifying novel prognostic and surrogate markers of oncogenic PKCι activity that may be clinically useful in ongoing clinical trials of ATM.
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http://dx.doi.org/10.1002/jcp.22463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075823PMC
April 2011

Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis.

Cancer Res 2010 Mar 23;70(5):2064-74. Epub 2010 Feb 23.

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Ciota (PKCiota) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCiota in pancreatic cancer. In this study, we evaluated the expression of PKCiota in human pancreatic cancer and the requirement for PKCiota for the transformed growth and tumorigenicity of PDAC cells. We find that PKCiota is significantly overexpressed in human pancreatic cancer, and high PKCiota expression correlates with poor patient survival. Inhibition of PKCiota expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCiota expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCiota effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCiota-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCiota in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCiota in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCiota will be an effective target for pancreatic cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-2684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881466PMC
March 2010

Protein kinase Cbeta is an effective target for chemoprevention of colon cancer.

Cancer Res 2009 Feb;69(4):1643-50

Departments of Cancer Biology and Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.

Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CbetaII (PKCbetaII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased beta-catenin accumulation. In this study, we test the hypothesis that PKCbetaII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCbeta-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCbetaII-mediated tumor cell proliferation and beta-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCbetaII- and beta-catenin/T-cell factor-regulated genes PKCbetaII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCbetaII is an important target for colon cancer chemoprevention and the PKCbeta-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745055PMC
February 2009

Protein kinase C betaII and PKCiota/lambda: collaborating partners in colon cancer promotion and progression.

Cancer Res 2009 Jan;69(2):656-62

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.

We previously showed that elevated expression of either protein kinase CbetaII (PKCbetaII) or PKCiota/lambda enhances colon carcinogenesis in mice. Here, we use novel bitransgenic mice to determine the relative importance of PKCbetaII and PKCiota/lambda in colon carcinogenesis in two complimentary models of colon cancer in vivo. Bitransgenic mice overexpressing PKCbetaII and constitutively active PKCiota (PKCbetaII/caPKCiota) or kinase-deficient, dominant-negative PKCiota (PKCbetaII/kdPKCiota) in the colon exhibit a similar increase in colon tumor incidence, tumor size, and tumor burden in response to azoxymethane (AOM) when compared with nontransgenic littermates. However, PKCbetaII/kdPKCiota mice develop predominantly benign colonic adenomas, whereas PKCbetaII/caPKCiota mice develop malignant carcinomas. In contrast, PKCbeta-deficient (PKCbeta(-/-)) mice fail to develop tumors even in the presence of caPKCiota. Our previous data indicated that PKCbetaII drives tumorigenesis and proliferation by activating beta-catenin/Apc signaling. Consistent with this conclusion, genetic deletion of PKCbeta has no effect on spontaneous tumorigenesis in Apc(min/+) mice. In contrast, tissue-specific knockout of PKClambda significantly suppresses intestinal tumor formation in Apc(min/+) mice. Our data show that PKCbetaII and PKCiota/lambda serve distinct, nonoverlapping functions in colon carcinogenesis. PKCbetaII is required for AOM-induced tumorigenesis but is dispensable for tumor formation in Apc(Min/+) mice. PKCiota/lambda promotes tumor progression in both AOM- and Apc(min/+)-induced tumorigenesis. Thus, PKCbetaII and PKCiota, whose expression is elevated in both rodent and human colon tumors, collaborate to drive colon tumor formation and progression, respectively.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-3001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688739PMC
January 2009

The high affinity peroxisome proliferator-activated receptor-gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane-treated mice.

Int J Cancer 2008 Sep;123(5):991-7

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA.

We evaluated RS5444, a thiazolidinedione high affinity PPARgamma agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARgamma expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARgamma activity was impaired in adenomas. To test this hypothesis, pre-existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444-treated mice. However, histological examination revealed that tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one-third of control tumors, but was never observed in RS5444-treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis.
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http://dx.doi.org/10.1002/ijc.23640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902358PMC
September 2008
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