bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-378: Establishment of hepatic metastases in a steatotic microenvironment is enhanced by stromal derived MMP-12
Authors: VanSaun Michael N. , Mendonsa Alisha , Lee In Kyu , Matrisian Lynn M. , Gorden Lee
Published: February 2011

Non-alcoholic fatty liver disease (NAFLD), encompassing steatosis and progression to non-alcoholic steatohepatitis (NASH) are liver disorders of increasing clinical significance. We have shown that hepatic steatosis establishes a permissive microenvironment for metastatic seeding and tumor progression in the liver. We have identified MMP-12 (macrophage metalloelastase) as an important molecular component associated with hepatic steatosis and steatohepatitis. Wildtype mice in the C57Bl/6 background were fed a 42% fat diet for three months to induce hepatic steatosis. Affymetrix microarray analysis was performed on steatotic vs. normal murine livers to determine candidate genes altered between these liver microenvironments. Our results noted 715 significant changes in gene expression, of which matrix metalloproteinase 12 was among the most significantly up regulated genes in the steatotic microenvironment. Importantly, we have detected an upregulation of MMP-12 in human steatotic and steatohepatitis samples. MMP-12 deficient mice gained weight and developed diet-induced hepatic steatosis similar to wildtype mice. To determine whether MMP-12 affected metastasis, normal and steatotic MMP-12 deficient mice were tested with an experimental metastasis model via splenic injection of MC38 tumor cells. The number of resultant tumors per unit of tissue area in wildtype steatotic livers showed a 25 fold increase compared to tumors in MMP-12 deficient mice. Comparison of tumors between regular diet livers in wildtype and MMP12−/−mice was not significant. Immunohistochemical staining for F4/80 showed a reduction in the number of positive cells in MMP-12 deficient steatotic livers.

Conclusions: Modulation of host factors is known to be important in tissue/site specific susceptibility to cancer metastases. MMP-12 can influence immune-mediated injury response by processing latent TNF alpha and regulating macrophage recruitment. Upregulation of matrix metalloproteinase 12 suggest a role for this protease in inflammatory mediated events in the distinct microenvironments of steatosis and steatohepatitis. The molecular mechanisms underlying the decreased establishment of metastatic tumors in MMP-12 deficient mice requires further investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-378.
Abstract LB-379: IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion
Authors: Gocheva Vasilena , Wang Hao-Wei , Gadea Bedrick , Shree Tanaya , Hunter Karen , Garfall Alfred , Joyce Johanna A.
Published: February 2011

Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin (IL)-4 is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-379.
Abstract LB-383: In vitro and in vivo MRI evaluation of a novel metallofullerene nanoparticle
Authors: Adiseshaiah Pavan P. , Stern Stephen T. , Ileva Lilia , Lenk Robert , Macfarland Darren , Kepley Chris L. , McNeil Scott E.
Published: February 2011

Some disadvantages of conventional small molecule contrast agents, such as Magnevist® (Gd - DTPA), are that they extravasate rapidly and are quickly eliminated from blood, limiting the viable MRI time. Macromolecular magnetic resonance imaging (MRI) contrast agents, on the other hand, are useful blood-pool agents and have found application in monitoring tumor vasculature and angiogenesis. There is an urgent need for new MRI contrast agents with higher relaxivity and longer blood half-life. Here, we report in vitro and in vivo characterization of a water-soluble derivatized fullerene nanoparticle contrast agent (NCL124) in comparison to the market standard, Magnevist. In comparison to Magnevist, NCL124 had higher R1and R2 relaxivities in human plasma at 22° C and 37°C. In vivo MRI imaging was performed on a LS174T dual-flank xenografts following a single intravenous injection of NCL 124 or Magnevist contrast agent (0.2 mmol Gd/Kg) using a 3.0 Tesla clinical whole-body MRI. Based on the relaxivity-time profiles, the Vss for NCL124 was similar to that of albumin (∼ 100 mL/Kg), suggesting high protein binding, while the Vss of Magnevist was similar to that of extracellular tissue water (∼200 mL/Kg), as expected for an extracellular diffusible tracer. NCL124 also had a longer blood half-life (∼ 100 min) than Magnevist (19 min). Taken together, the higher concentration (Cmax) and exposure (AUCall) of NCL124 in the blood, coupled with slow elimination, supports the use of NCL124 as a blood-pool contrast agent. Intriguingly, the half-life of NCL124 varied by tumor size, while Magnevist showed similar half-life in both tumors. This suggests NCL124 may have significant utility in predicting differences in tumor vascular and lymphatic permeability, and potentially be useful as a marker for antiangiogenic therapy. Funded by NCI contract # HHSN261200800001E.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-383.
Abstract LB-384: Targeting overexpressed Aurora kinases in childhood medulloblastoma: Antiproliferative effects of small molecule inhibitors ZM44739, VX680 and shRNA
Authors: Holst Martin I. , Westerhout Ellen , Kool Marcel , Versteeg Rogier , Caron Huib , Clifford Steve , Rutkowski Stefan , Pietsch Torsten
Published: February 2011

Kids Cancer Kinome (KCK) is a European research project investigating aggressive childhood cancers. Focusing on the human protein kinase family nine research centers explore different highly malignant pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets and develop novel therapeutic options.

Medulloblastomas of the cerebellum represent the most frequent malignant brain tumors of childhood. Previous studies revealed Aurora kinase A (STK15) as independent predictor for an unfavorable outcome of medulloblastoma patients. The Aurora kinases belong to the family of serine/threonine kinases which are involved in the cell cycle by controlling chromatid segregation. It is commonly approved, that defects in the process of cell division are associated with tumorigenesis.

Using mRNA expression profiling (Affymetrix) we compared the Aurora kinase mRNA expression of 62 medulloblastoma tumor samples with normal cerebellar tissue (n=9) and an extensive dataset of various other tumor types (n=2028). We discovered a significant overexpression of Aurora kinase mRNA in primary medulloblastoma tumors, as well as 14 medulloblastoma cell lines compared to non-neoplastic tissues (n=685). Kaplan-Meier scans revealed an inverse correlation between overall survival rates and mRNA expression levels of Aurora kinases.

To investigate the effects of Aurora kinase inhibition on medulloblastoma cells, we first evaluated the effects of the small molecule inhibitors ZM447439 andVX680 on the proliferation of medulloblastoma cell lines. Incubation of medulloblastoma cells with ZM447439 and VX680 for 72h resulted in a concentration dependent decrease of the proliferative activity as measured by MTS proliferation assays. The GI50 for ZM447439 ranged from 0.2 to 20 µm and for VX680 from 0.02 to 10.0 µm. Cytologically, the cells appeared enlarged and multinucleated after Aurora kinase inhibition. In a second approach, we transduced cell lines with lentiviral particles carrying shRNA targeting Aurora A and B kinase. The specific downregulation of the Aurora kinases with lentiviral shRNA was confirmed by Western blotting and had a negative effect on the viability of the medulloblastoma cells. In conclusion, these data suggest that the inhibition of Aurora kinases may represent a promising approach for novel targeted strategies for the treatment of medulloblastoma.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-384.
Abstract LB-385: The Hippo pathway component YAP1 promotes cerebellar precursor survival after irradiation and can accelerate medulloblastoma onset
Authors: Fernandez-L Africa , Squatrito Massimo , Kenney Anna M.
Published: February 2011

Medulloblastoma is the most common malignant solid tumor in children. These tumors arise in the developing cerebellum, a region of the brain that undergoes rapid expansion after birth. Current treatments for medulloblastoma include radiation, surgery and chemotherapy, all of which are associated with devastating physical and mental side effects in long-term survivors. Recently, cells within medulloblastomas that survive radiation treatment and can repopulate the tumors post-radiation have been identified. These cells reside in regions adjacent to blood vessels, and their post-radiation survival is promoted by PI3 kinase pathway activity. Ideal medulloblastoma therapies will attack the tumors and eliminate the tumor re-initiating cells but spare the rest of the brain. We have recently published that the oncogenic transcriptional co-activator YAP1, which is negatively regulated by the Hippo pathway, is up regulated and amplified in a subset of human medulloblastomas with aberrant Sonic hedgehog (Shh) signaling. YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly-growing tumor cells. We report here that YAP1 is actively involved in survival post-irradiation. CGNPs that over-express YAP1 in vitro proliferate more and present less apoptosis after irradiation than those over-expressing GFP. Among YAP1 target genes in CGNPs we found Securin, which, apart from its known role in mitosis, it has been shown to have roles in survival after DNA damage. We also found Securin highly expressed in human and mouse medulloblastomas. Moreover, injection of YAP 1 over-expressing medulloblastoma cells in postnatal day 4 wild type mice accelerate medulloblastoma onset compared to GFP over-expressing cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-385.
Abstract LB-396: Site-specific risk factors for colorectal cancer among Korean population
Authors: Shin Aesun , Bak Jeongin , Kim Jeongseon , Park Sohee , Nam Byung-Ho
Published: February 2011

Colorectal cancer incidence and mortality have been gradually increasing during the last few decades in Korea. Growing evidences revealed etiological differences among proximal colon, distal colon, and rectal cancer. Furthermore, the proportion of rectal cancer among colorectal cancer incidence in Korean people is over 40%. This is relatively high compared to that observed among Western population. We investigated the association between colorectal cancer risk factors and different sites of colorectal cancers based on a large Health Insurance Study.

Included in this study were 869,725 men and 395,501 women who were beneficiaries or dependent family members of the insured who were cancer-free at baseline between 1996 and 1997, participating in the National Health Insurance Corporation Study (NHICS) were followed for up to 7 years. The Cox proportional hazard model was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) with adjustment for age. During up to 7 years of follow-up, 4,144 incident colorectal cancer cases were detected (3,051 men and 1,093 women). Height was associated with an elevated risk for left colon cancer and rectal cancer in men (HR=1.02, 95% CI=1.01-1.03 for left colon cancer and HR=1.01, 95% CI=1.00-1.02 for rectal cancer, per 1 cm increments) and that for rectal cancer in women (HR=1.03, 95% CI=1.01-1.04, per 1 cm increments). Family history of cancer was associated with a higher risk for cancer of right colon (HR=1.40, 95% CI=1.14-1.72) and left colon (HR=1.31, 95% CI=1.12-1.55) in men, and for cancer of left colon (HR=1.57, 95% CI=1.20-2.06) in women. Frequent alcohol consumption and high consumption amount were associated with an elevated risk for left colon cancer in men. Men who consumed alcoholic beverages 3-4 times per week showed 1.65-fold increase risk for left colon cancer compared to non-drinkers (95% CI=1.32-2.06, p-trend<0.001). Whereas frequent alcohol consumption was associated with a higher risk for rectal cancer in women (HR=2.75, 95% CI=1.61-4.71 for almost every day vs. non-drinkers). Frequent meat consumption was associated with risk for right colon cancer in both men (HR=1.37, 95% CI=0.99-1.91 for ≥4 times/week vs. ≤1 time/week) and women (HR=1.72, 95% CI=1.11-2.66 for ≤4 times/week vs. ≤1 time/week), and that for rectal cancer in women (HR=1.46, 95% CI=1.05-2.03 for ≥4 times/week vs. ≤1 time/week). Our findings support the hypothesis of differential risk factor profiles according to subsites of colorectum, and suggest that colon cancer is more susceptible to host factors such as family history of cancers, and distal colon cancer and rectal cancer are more susceptible to environmental risk factors such as alcohol consumption.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-396.
Abstract LB-400: Conventional and anti-microbial pesticide exposures and increased risk of lung cancer in Mexican Americans
Authors: McHugh Michelle K , Kachroo Sumesh , Liu Mei , D'Amelio Anthony M. , Dong Qiong , Greisinger Anthony , Hong Waun Ki , Spitz Margaret R. , Etzel Carol J.
Published: February 2011

Objective: We investigated demographic factors, environmental and occupational exposures, and medical and family cancer histories in a population of Mexican-American lung cancer cases and controls from the Houston Metropolitan area.

Methods: Data were collected as a part of a multi-racial/ethnic on-going lung cancer case-control study. Cases included 212 Mexican American lung cancer cases. Controls (n=328) were recruited from Houston's largest multispecialty group practice and frequency matched to the cases by age (±5 years), sex and ethnicity. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. Environmental and occupational factors were analyzed individually; however pesticides were analyzed as: 1) any exposure to conventional or antimicrobial pesticides; 2) exposure to conventional pesticides only; and 3) exposure to antimicrobial pesticides only.

Results: We detected elevated risks of lung cancer associated with asbestos, wood dust, fibers, SVF, benzene, toluene/xylene, dry cleaning fluids, vehicle exhaust, glues and plastics; however only pesticide exposure was statistically significant. We found both conventional and anti-microbial pesticide exposures were associated with an increased risk of lung cancer in Mexican Americans (conventional pesticides and antimicrobial pesticides combined: OR=1.80, 95%CI 1.13-2.86; conventional pesticides: OR=2.05, 95% CI 1.23-2.39; and anti-microbial pesticides: OR=2.48, 95% CI 1.46-4.21).

Conclusions: Although we found over a two-fold increased risk of lung cancer among Mexican Americans for conventional and anti-microbial pesticides, we were not able to identify individual pesticides. Our findings are descriptive in nature and we believe are a necessary and important preliminary step in identifying factors that are specifically associated with lung cancer risk among this minority subgroup.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-400.
Abstract LB-410: A single nucleotide polymorphism in human PIGK gene associates with low PIGK expression in colorectal cancer patients
Authors: Dasgupta Santanu , Fu Yumei , Nissan Aviram , Halle David , Sidransky David , Trink Barry
Published: February 2011

Colorectal cancer (CRC) has one of the highest incidences of cancers worldwide and is the fourth most common cancer among men and women in the United States. In Israel, approximately 3000 new CRC cases are being diagnosed annually, representing 13% of all new cases. CRC ranks second in the total number of cancer cases both in the Jewish male and female population. It is uncommon in the non-Jewish (Arab) population.

Phosphatidylinositol glycan, class K (PIGK) is an integral member of the Glycosylphosphatidylinositol transamidase (GPIT) protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. It is well established that PIGK catalyzes the endoproteolysis and amidation steps involved in transfer of a GPI-anchor to proteins. However, the role of PIGK in tumorigenesis remains largely unknown. Recently, we found a markedly low expression of PIGK protein in some colorectal cancer (CRC) patients. In order to understand the mechanism behind, we examined all the 10 exons of the PIGK gene by DNA sequencing and genotyping in 20 CRC patients from Israel (16 Jews and 4 Arabs). Corresponding expression of the PIGK protein was also determined by immunohistochemistry in all the above CRC patients. We found a single nucleotide polymorphism (C/C C/G or G/G; rs1048575) in the 3′UTR of the PIGK gene in 65% (13/20) of the CRC patients. Most of the patients with the altered genotype were Jews (12 vs. 1). Three out of four Arab patients (75%) exhibited the ancestral C/C genotype. We also observed a significantly low (P<0.002) expression of PIGK protein in all the patients with the altered allele (C/G or G/G) compared to the ancestral alleles (C/C). Similar observation was made on PIGK expression in a couple of transformed human colon cell lines with the ancestral (C/C) and altered (/C/G) genotype. Our results demonstrate for the first time a link between the SNP-1048575 and low PIGK expression in CRC patients and also suggest a possible association between altered PIGK expression and CRC susceptibility.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-410.
Abstract LB-411: Genotype and haplotype analysis of cell cycle genes and the risks of sporadic colorectal and pancreatic cancers in the Czech Republic
Authors: Vodicka Pavel E. , Naccarati Alessio , Pardini Barbara , Polakova Veronika , Smerhovsky Zdenek , Vodickova Ludmila
Published: February 2011

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. Pancreatic carcinoma represents the fourth leading cause of cancer-related deaths in the country, with a minimum of patients surviving 5 years. The etiology and molecular pathogenesis of above cancers are weakly understood. TP53 plays a role in cell cycle and apoptosis and is frequently mutated in solid tumors, including colorectal and pancreatic. Assuming that genetic variation may affect susceptibility to cancer development, the role of polymorphisms and haplotypes of TP53, CDKN1A and CDKN2A in modulating the cancer risk was addressed.

We investigated selected polymorphisms in TP53 (rs17878362:A1>A2, rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital-based cases and 614 matched controls from the country for association with colorectal cancer and 240 cases and controls (for a total of 1827 individuals) for association with pancreatic cancer risk.

For CRC, none of the studied polymorphisms was strongly associated with risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). In comparison to the most common haplotype (A1GCG), the haplotype A2CCG was associated with an increased risk (OR 1.40, 95% CI 1.07-1.82), while four other less frequent haplotypes A1CCG, A2GCG A1GTG, and A1GCA were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon and rectal cancers. No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. For pancreatic cancer: carriers of the variant C allele of rs1042522 polymorphism were at an increased risk of (OR 1.73; 95% CI 1.26-2.39; p=0.001). The A2CCG haplotype in comparison with the most common haplotype (A1GCG) was associated with an increased risk (OR 1.39; 95% CI 1.02-1.88; p=0.034), and the A1CCG with a reduced risk (OR 0.30; 95% CI 0.12 -0.76; p=0.011) for this cancer. Genetic variation in TP53 may contribute, alone or in concert with other risk factors, to modify the inherited susceptibility to both colorectal and pancreatic cancers, as well as to other gastrointestinal cancers.

Supported by GACR 310/07/1430.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-411.
Abstract LB-414: Variation in base excision repair genes and risk of smoking-related non-small cell lung cancer
Authors: Brenda Diergaarde , Buch Shama , Nukui Tomoko , Day Roger , Siegfried Jill , Weissfeld Joel , Romkes Marjorie
Published: February 2011

Base excision repair (BER) is the primary mechanism responsible for the repair of small base lesions in DNA caused by oxidation and alkylation. Given this role, functionally relevant polymorphisms in BER pathway genes may well affect the risk of smoking-related non-small cell lung cancer (NSCLC). We examined the association between 49 single nucleotide polymorphisms (SNPs) located in or near 5 different BER genes (XRCC1, LIG1, PARP1, MPG, and OGG1) and risk of NSCLC among Caucasians in a large case-control study. The study population consisted of 599 cases and 934 controls; all study participants were Caucasian and current or former cigarette smokers who had smoked at least 10.0 pack-years. SNPs were selected using various resources including literature review and data from the International HapMap project, and genotyping was conducted by Illumina Goldengate assay. Deviation from Hardy-Weinberg equilibrium was evaluated with the exact method. Associations between alleles and genotypes and NSCLC risk were examined using a Pearson Chi-square test and a Cochran-Armitage trend test, respectively. Per (minor) allele odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were also calculated for each SNP. Six SNPs (rs3219073, rs747658, rs3219090, rs2048424, rs2666428, and rs8679) in PARP1 were statistically significantly (P<0.01) associated with NSCLC risk in our study population. SNP rs3219073 was in high linkage disequilibrium (r2≥0.8) with rs747658, as were rs3219090 and rs2048424 with rs2666428. The minor alleles of these SNPs were associated with a decreased risk of developing NSCLC (rs747658, OR: 0.7, 95%CI: 0.6-0.9, Ptrend=0.0005; rs2666428, OR: 0.8, 95%CI: 0.7-0.9, Ptrend =0.005). The C allele of SNP rs8679 (3′ UTR) was associated with an increased risk of NSCLC (OR: 1.3, 95%CI: 1.1-1.5, Ptrend =0.005). Additionally, SNPs rs3213255 and rs1799782 (Arg194Trp) in XRCC1 and SNP rs10500298 in LIG1 were also significantly associated with NSCLC risk. The minor alleles of rs3213255 and rs10500298 were associated with an increased risk (OR: 1.3, 95%CI: 1.1-1.5; OR: 1.2, 95%CI: 1.1-1.4, respectively), while the minor allele of rs1799782 was associated with a decreased risk (OR: 0.6, 95%CI: 0.4-0.9). PARP1 polymorphisms have previously been reported associated with other cancers, including breast cancer and colorectal cancer, but this is the first study to report associations with NSCLC risk. To conclude, our results suggest that common variation in PARP1, XRCC1 and LIG1 may be associated with risk of smoking-related NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-414.
Abstract LB-42: PDK1 knockdown selectively inhibits growth of cancer cells harboring activating mutations involved in MAPK signaling
Authors: DeYoung M. Phillip , Gardiner Christine M. , Chadderton Antony R. , Medina Jesus R. , Axten Jeffrey M. , Rabindran Sridhar K.
Published: February 2011

Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway which is the most commonly deregulated signaling pathway across all cancers. Increased PDK1 activity confers chemoresistance in tumor cell lines, and reduced PDK1 expression prevents the onset of tumorigenesis in mouse models. To demonstrate that PDK1 is a promising target for cancer therapy, we used a siRNA-based approach to determine the effects of PDK1 knockdown in cancer cells and primary early-passage normal cells. Loss of PDK1 protein caused a significant reduction in phosphorylation of two PDK1 substrates, AKT (T308) and RSK1 (S221). Interestingly, knockdown of PDK1 protein had preferential growth inhibitory effects in cancer cells containing activating mutations of KRAS or BRAF, compared to cells with wild-type KRAS or BRAF. In KRAS/BRAF-mutant cells, apoptosis was evidenced by PARP-1 cleavage and an increase in the number of sub-G1 DNA content. Overexpression of mouse PDK1 rescued these cells from apoptosis, confirming the specificity of the siRNA-mediated effects. Consistent with these observations, stable expression of mutant KRAS (G12V) in NL-20 immortalized normal lung epithelial cells sensitized these cells to apoptosis upon knockdown of the PDK1 protein. Importantly, overexpression of a kinase-dead mouse PDK1 mutant did not rescue cells from apoptosis, suggesting that the kinase activity is required for these PDK1 functions. Based on these results, we sought to identify inhibitors of the kinase activity of PDK1 for development as anticancer agents. GSK2334470 was identified as a potent inhibitor of PDK1 kinase (IC50 0.5 nmol/l) that demonstrated a high level of specificity to PDK1 in an in vitro kinase panel. In cell-based mechanistic assays, GSK2334470 effectively inhibited phosphorylation of the PDK1-dependent phosphorylation sites [AKT T308 (IC50: 100 nmol/L) and RSK S221 (IC50: 291 nmol/L)], but not the PDK1-independent phosphorylation site on AKT, S473 (IC50: >30 umol/L). Antiproliferative effects were seen in several cell lines using low micromolar concentrations of inhibitor; however, no correlation between growth inhibition and KRAS/BRAF mutations was observed. Further optimization may be necessary for improved potency and KRAS/BRAF selectivity. Currently, efforts are underway to better understand the disconnect between siRNA data and compound data in several experimental cancer models, particularly in those where KRAS or BRAF mutations predominate.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-42.
Abstract LB-427: Differential effects of resveratrol-induced SIRT1 in prostate cancer: A novel therapeutic target
Authors: Li Guiming , Ghosh Rita , Kumar Addanki P.
Published: February 2011

Silence information regulator (SIRT1) is a Nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that regulates various biological processes including cell survival, apoptosis, metabolism and aging. Given the role for calorie restriction (CR) in delaying the onset of aging and age-related disorders including cancers, efforts are under way to develop CR mimetics as therapeutic agents. Resveratrol, a CR mimetic activates SIRT1 and has been shown to extend life span. Further, resveratrol has been shown to prevent tumor development and cancer cell proliferation in a wide variety of models including prostate. However the precise role of SIRT1 in prostate cancer development and progression remains unexplored. Towards developing SIRT1 targeted preventive approaches, we conducted studies using human prostate cancer cell lines and a preclinical animal model that develops high grade prostatic intraepithelial neoplasia (HGPIN) in response to hormone stimulation. Our studies show that androgen independent prostate cancer cell lines (DU145 and PC-3) express higher levels of SIRT1 compared to non tumorigenic RWPE-1 consistent with the published results. Resveratrol-mediated inhibition of cell proliferation was associated with reduction in the levels of pAkt (Ser473 and Thr308), SIRT1and Cyclin D1 in PC-3 cells but not in DU145. Most interestingly we did not detect SIRT1 enzymatic activation following resveratrol treatment. Further pretreatment of prostate cancer cells with known pharmacological SIRT1 inhibitor (Nicotinamide) enhanced resveratrol mediated proliferation inhibition. Dietary intervention with increasing doses of resveratrol for 3 weeks showed no protective effect on the development of PIN lesions or chronic inflammation or atrophy in rats stimulated with hormones. Our studies show for the first time that (i) SIRT1 may not be a direct target of resveratrol; (ii) combination of resveratrol and SIRT1inhibitor may provide a new approach to prevent development and progression of prostate cancer. Supported by CA 137518 (APK).

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-427.
Abstract LB-431: Randomized trial of oral melatonin supplementation in breast cancer survivors
Authors: Schernhammer Eva S. , Giobbie-Hurder Anita , Gantman Kathryn , Savoie Jennifer , Scheib Rochelle , Chen Wendy
Published: February 2011

Background: Night shift work has been classified by the International Agency for Research and Cancer and the World Health Organization as a probable carcinogen, presumably due to its effect on the melatonin pathway. Extensive laboratory and some human data also support that melatonin may influence breast cancer risk, although the mechanism is not clear. Both pharmacologic and physiologic doses of melatonin inhibit the growth of malignant cells of the breast in vitro and in animal models.

Study Design: 95 postmenopausal women with a prior history of Stage 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were recruited to a double-blind randomized trial of 4 months of 3 mg melatonin daily compared to placebo. Endpoints included changes in breast cancer biomarkers, sleep, hot flashes, and mood.

Results: 5 subjects on melatonin and 4 on placebo withdrew from the study or did not complete the 4 month assessment leaving 86 women (43 on placebo and 43 on melatonin) with evaluable data. Melatonin was well-tolerated without any grade 3/4 toxicity. At baseline, there was no statistical difference between the two arms for any of the endpoints or standard demographic characteristics. Mean age was 59 years (range 38-71) with mean 8 years since diagnosis. At 4 months, there were no statistically significant differences between the two groups for the biomarker endpoints (estradiol, IGF-1, IGFBP-3, or IGF-1/IGFBP-3 ratios), depressive symptoms, or hot flashes. However, subjects taking melatonin had significantly improved sleep quality, sleep duration, and total sleep scores compared with subjects taking placebo.

Conclusions: Among postmenopausal women with a prior history of breast cancer, a 4 month course of 3 mg melatonin daily did not influence IGF-1, IGFBP-3 or estradiol levels. Effects of longer courses of melatonin and among premenopausal women are unknown. However, melatonin was effective in improving sleep quality among breast cancer survivors without any significant adverse effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-431.
Abstract LB-45: Cancerous inhibitor of phosphatase PP2A in lung cancer
Authors: Zhou Guangbiao , Ma Liang , Wen Zhesheng
Published: February 2011

Cellular signaling networks are controlled by reversible covalent phosphorylation, which depends on a precise balance between protein kinase and phosphatase activities. Recently, phosphatase has been shown to be silenced by cancerous inhibitor of phosphatase, leading to perturbation of the kinase/phosphatase balance. Here we report that at mRNA and protein levels, the expression of the cancerous inhibitor of phosphatase PP2A (CIP2A) were undetectable or very low in paratumor tissues, but was dramatically elevated in tumor samples in 33 (63.%) out of 52 patients. CIP2A enhanced clonogenic activity of human embryo lung fibroblast, while CIP2A silencing by siRNA led to inhibition of cell proliferation and induction of apoptosis of lung cancer cells. We found that LTZ010 which was a compound extracted from a traditional Chinese medicinal herb, triggered a rapid turnover of CIP2A, and increased PP2A phosphatase activity. At presence of proteasome inhibitor PS-341, aggresome was found in cytoplasm of cells treated with LTZ010, and catabolism of CIP2A was abrogated. We found that LTZ010 inhibited proliferation and cell growth of lung cancer cells, and activated caspase-9 and -8. Intriguingly, LTZ010 significantly inhibited tumor growth in vivo, but did not caused animal body weight loss. Our data suggest that CIP2A might play an important role in lung cancer tumorigenesis, and LTZ010 might have potential benefits for patients with lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-45.
Abstract LB-47: Resveratrol induces Apaf-1 dependent but apoptosome-independent apoptosis in cancer cells
Authors: Prabhu Varun V. , Amadori Michael , Zhang Honghao , Pitaressi Jason , Yadav Neelu , Chandra Dhyan
Published: February 2011

Resveratrol (Resv) selectively kills cancer cells, whereas the molecular mechanisms of Resv-induced cancer cell death are not defined. Here we show that Resv induces mitochondria-dependent but apoptosome-independent apoptosis in cancer cells. Resv inhibits cancer cell growth and proliferation, mitochondrial membrane potential, and ROS production. In contrast, Resv induces dose and time dependent caspase activation, poly (ADP-ribose) polymerase (PARP) cleavage, and thus caspase-dependent apoptosis. Mechanistic analysis reveals that recruitment and oligomerization of Bax on the mitochondria is associated with release of cytochrome c from the mitochondria. Surprisingly, the released cytochrome c fails to induce apoptosome assembly as evidenced by the lack of Apaf-1 oligomerization upon Resv treatment. Interestingly, Apaf-1 was up regulated both at transcriptional and protein levels upon Resv treatment suggesting that the levels of Apaf-1 was not a limiting factor for apoptosome assembly. Subcellular analysis reveals that catalytically active caspase-9 was mostly associated with the mitochondria in Resv-induced apoptotic cells. Reconstitution experiment using recombinant proteins and purified cytosols demonstrates that Resv inhibits apoptosome functions in a dose dependent manner. MALDI-TOF analysis indicates that inhibition of apoptosome formation was not mediated by sequestration of cytochrome c as Resv fails to interact with cytochrome c. Furthermore, Resv also induces autophagy as evidenced by the increase in the levels of LC3-II upon Resv treatment. Inhibition of autophagy either by autophagy inhibitors or by silencing of autophagy related genes (ATG-5 or Beclin-1) further increase caspase activation. Gel filtration and subcellular fractionation analyses demonstrate that caspase-independent apoptosis does not seem to be involved as AIF and endonuclease G was not released from the mitochondrial compartment upon Resv treatment. These findings indicate that Resv targets mitochondria to induce caspase-9 mediated cancer cell death and that induction of autophagy during apoptosis is an adaptive response. Therefore, inhibition of autophagy along with induction of apoptosis could represent a novel strategy for cancer therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-47.
Abstract LB-51: Correlation of expression of MDR-associated genes with outcome in primary ovarian serous carcinoma
Authors: Gillet Jean-Pierre , Calcagno Anna Maria , Varma Sudhir , Davidson Ben , Elstrand Mari Bunkholt , Ganapathi Ram , Sood Anil K. , Ambudkar Suresh V. , Seiden Michael V. , Rueda Bo R. , Gottesman Michael M.
Published: February 2011

We have been developing tools to reproducibly correlate the expression of multidrug-resistance (MDR)-associated genes with response to chemotherapy in primary cancers. This study reports the results of a novel MDR gene expression analysis of primary serous carcinoma of the ovary utilizing a TaqMan Low Density Array (TLDA) chip which includes 380 previously characterized multidrug resistance (MDR)-associated genes that were initially identified in cultured cancer cells. Primary tumor samples from 133 patients from 4 sites were studied. All patients were subsequently treated with standard chemotherapy and had known clinical outcome. A 13 gene signature was identified whose expression added statistical power to the risk status of the patients based on standard clinical parameters (age, CA125, and success of surgical debulking) (log-rank statistic p=0.02). When subsets of patients with defined clinical risk were studied, we found that a subset of clinically high risk patients that had low expression of the 13 gene signature had a better outcome than would be predicted by purely clinical criteria. Similarly, clinically low risk patients with high expression of the 13 gene signature had a poorer prognosis. Since the mechanism of action of the 13 MDR genes involved in the signature are well-understood, it might be possible to devise therapeutic strategies to some of these targets with the goal of improving clinical outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-51.
Abstract LB-6: bHLH transcription factor Id4 plays a regulatory role in cell cycle control, apoptosis, and senescence in androgen-insensitive prostate cancer
Authors: Jason Carey P. , Chaudhary Jaideep , Evans Ashley
Published: February 2011

Id4 belongs to a family of genes that are dominant negative regulators of basic helix-loop-helix (bHLH) transcription factors. Id4 expression shows an inverse correlation to Id1-3 expression in advanced metastatic prostate cancer which act as tumor promoter genes. Recent Id4 promoter hypermethyation data suggests that Id4 may act as a tumor suppressor in prostate cancer, and loss of Id4 expression may correlate with androgen insensitive prostate cancer progression. The inhibitory role of Id4 is characterized by inhibition of cancer progression and up regulation of tumor suppressor genes. In the DU145 prostate cancer cell line, Id4 down regulation is responsible for increased cell survival, metastasis and decreased apoptosis. Id4 absent/androgen-independent prostate cancer cell line DU145 was used to ectopically express Id4 mRNA and protein. This allowed for a novel identification of the role Id4 plays in cell cycle control, apoptosis and proliferation in an advanced prostate cancer model. FACS analysis highlighted the role of Id4 in cell cycle maintenance. Apoptosis assays support the tumor suppressor role of Id4 in DU145 cell lines. Senescence assays were also conducted on in Id4 expressing DU145 cells. RT-PCR and western blot analysis were used to study gene expression of downstream apoptosis and cell cycle control genes E-cadherin, p21, p27, p53, MDM2, E2F1 and, Androgen receptor. Du145 + Id4 prostate cancer cells have significantly decreased proliferation due to an S-phase arrest possibly associated with E2F-1 down regulation. The increased expression of E-cadherin, p27, p21 and p53 strengthens the hypothesis of Id4 as a tumor suppressor by regulating key cell cycle control and apoptosis associated genes. A functional androgen receptor was also induced in this androgen insensitive prostate cancer model. Id4 ectopic expression resulted in a significant decrease in Id1 and Id3, which are known contributors to metastasis and cell survival. This suggests that Id4 may inhibit bHLH transcription factors involved in proliferation, and metastasis of prostate cancer cells. Id4 induces apoptosis whether dependent/independent of the mutated p53 gene in DU145 cells. The presence of senescent cells in Id4 transfected cell lines suggest that Id4 may also play a role in autophagic cell death. We conclude that the mechanism by which Id4 may act as a tumor suppressor is by influencing a hierarchy of cellular processes at multiple levels including, apoptosis, senescence and S-phase mediated cell cycle arrest, which results in changes to cell morphology, and androgen receptor response.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-6.
Abstract LB-7: Epigenetic silencing of IRF8 expression is associated with myeloid leukemia escape from cancer immunosurveillance
Authors: Hu Xiaolin , Liu Kebin
Published: February 2011

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease (MPD) that comprises 15-20% of human hemapoietic cancers. Exciting advances in molecular mechanism-based strategies have yielded imatinib mesylate/STI571/Gleevec, which has proven to be effective in many human patients with CML. Unfortunately, Gleevec is not effective in some human CML patients, whereas some CML patients become refractory to Gleevec due to the development of drug resistance caused by mutations in abl. Furthermore, Gleevec becomes significantly less effective if the CML evolves to blast crisis. Therefore, elucidating the molecular mechanisms underlying CML pathogenesis is of significance for the development of more effective molecular target-based therapy for CML patients. In this study, we demonstrated that the IRF8 expressed is decreased in human CML/AML cells and the IRF8 promoter is methylated in human CML/AML cells and in PMBC derived from human CML patients. Ectopic expression of IRF8 in myeloid cells suppressed tumor development in mice in vivo. We further demonstrated that IRF8 regulates Fas and FLIP expression in myeloid leukemia cells to mediated Fas-mediated apoptosis. Taken together, our data suggest that myeloid leukemia cells use DNA methylation to silence IRF8 expression to acquire a Fas-resistant phenotype to escape from cancer immunosurveillance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-7.