bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia
Authors: Rago Florencia , Rodrigues Lindsey Ulkus , Bonney Megan , Sprouffske Kathleen , Kurth Esther , Elliott GiNell , Ambrose Jessi , Aspesi Peter , Oborski Justin , Chen Julie T. , McDonald E. Robert , Mapa Felipa A. , Ruddy David A. , Kauffmann Audrey , Abrams Tinya , Bhang Hyo-eun C. , Jagani Zainab
Published: March 2024

Abstract
Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myelogenous leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared with other lineages. This result was striking in comparison with data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes, including MYC, a well-established target of BRG1 activity in AML. Overall, small-molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes.
Implications:
Our studies reveal the breadth of SWI/SNF dependency in leukemia and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.
Data from RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions
Authors: Cho Jung-Hyun , Park Soyoung , Kim Soyeong , Kang So-Mi , Woo Tae-Gyun , Yoon Min-Ho , Lee Hyunkee , Jeong Myeonggyo , Park Yeong Hye , Kim Heegyu , Han Young Taek , Suh Young-Ger , Kim Bae-Hoon , Kwon Yonghoon , Yun Hwayoung , Park Bum-Joon
Published: March 2024

Abstract
Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGFβ signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST.
Implications:
This study identifies that a selective RKIP inducer inhibits tumor growth and promotes schwannoma cell differentiation under NF2-deficient conditions by reducing SOX2 and increasing SOX10 expression.
Data from Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4
Authors: Mittal Karuna , Kaur Jaspreet , Sharma Shaligram , Sharma Nivya , Wei Guanhao , Choudhary Ishita , Imhansi-Jacob Precious , Maganti Nagini , Pawar Shrikant , Rida Padmashree , Toss Michael S. , Aleskandarany Mohammed , Janssen Emiel A. , Søiland Håvard , Gupta Meenakshi. V. , Reid Michelle D. , Rakha Emad A. , Aneja Ritu
Published: March 2024

Abstract
Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is understudied. The aim of this study was to examine the role of hypoxia in promoting CA via PLK4. We found that hypoxia induced CA via hypoxia-inducible factor-1α (HIF1α). We quantified the prevalence of CA in tumor cell lines and tissue sections from breast cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and prostate cancer and found that CA was prevalent in cells with increased HIF1α levels under normoxic conditions. HIF1α levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1A mRNA levels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1α in breast cancer and PDAC prognosis. High HIF1A and PLK4 levels in patients with breast cancer and PDAC were associated with poor overall survival. We confirmed PLK4 as a transcriptional target of HIF1α and demonstrated that in PLK4 knockdown cells, hypoxia-mimicking agents did not affect CA and expression of CA-associated proteins, underscoring the necessity of PLK4 in HIF1α-related CA. To further dissect the HIF1α-PLK4 interplay, we used HIF1α-deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1α-deficient cells harboring wild-type PLK4. These findings suggest that HIF1α induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers.
Implications:
Hypoxia drives CA in cancer cells by regulating expression of PLK4, uncovering a novel HIF1α/PLK4 axis.
Data from Serum Insulin-like Growth Factor-I and Mammary Tumor Development in Ad libitum–Fed, Chronic Calorie–Restricted, and Intermittent Calorie–Restricted MMTV-TGF-α Mice
Authors: Rogozina Olga P. , Bonorden Melissa J.L. , Grande Joseph P. , Cleary Margot P.
Published: March 2024

Abstract
The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. Ten-week-old MMTV-TGF-α female mice were assigned to ad libitum–fed (AL; AIN-93M diet), ICR [3-week 50% caloric restriction using AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3 weeks of daily 100% AL consumption of AIN-93M (∼75% of AL for each 6-week cycle)], and CCR (calorie and nutrient intake matched for each 6-week ICR cycle) groups. Half of the mice from each group were sacrificed at 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum was obtained at euthanasia and in cycles 1, 3, 5, 8, and 11. MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICR-Restricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. There were no differences in terminal IGFBP-3. Final body, internal, and mammary fat pad weights correlated positively with IGF-I and negatively with IGFBP-3. Few changes were found for protein expression of IGF-IRα and IGFBP-3 in mammary tissue and MTs. During the study, IGF-I levels of ICR-Restricted mice were reduced, whereas refeeding allowed partial recovery. For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR.
Data from Incremental Value of Pulmonary Function and Sputum DNA Image Cytometry in Lung Cancer Risk Prediction
Authors: Tammemagi Martin C. , Lam Stephen C. , McWilliams Annette M. , Sin Don D.
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer death worldwide. Accurate prediction of lung cancer risk is of value for individuals, clinicians, and researchers. The aims of this study were to characterize the associations between pulmonary function and sputum DNA image cytometry (SDIC) and lung cancer, and their contributions to risk prediction. During 1990 to 2007, 2,596 high-risk individuals were enrolled and followed prospectively for development of lung cancer (n = 139; median follow-up 7.7 years) in trials at the British Columbia Cancer Agency. At baseline, an epidemiologic questionnaire was administered, sputum was collected for aneuploidy measurement and spirometry was obtained. Multivariable logistic models were prepared including known lung cancer predictors (model 1), that additionally included percent-expected-forced expiratory volume in 1 second [forced expiratory volume in 1 second (FEV1%), model 2], and that additionally included SDIC (model 3). Prediction was assessed by evaluating discrimination (receiver operator characteristic area under the curve (ROC AUC)) and calibration. Net reclassification indices (NRI) were calculated with cutoff points for 8-year risks identifying low, intermediate, and high risk at 1.5% and 3%. Lung cancer risk increased with decline in FEV1%, but did so more for men than for women (interaction P < 0.001). SDIC demonstrated a dose–response with lung cancer (P = 0.022). The ROC AUCs for models 1, 2, and 3 were 0.718 (95% CI: 0.671–0.765), 0.767 (95% CI: 0.725–0.809), and 0.773 (95% CI: 0.732–0.815), respectively. Model 2 versus 1 had a NRI of 12.6% (P < 0.0001) and model 3 versus 2 had a NRI of 3.1% (P = 0.059). Spirometry and SDIC data substantially and minimally improved lung cancer prediction, respectively. Cancer Prev Res; 4(4); 552–61. ©2011 AACR.
Data from Chemoprevention Activity of Dipyridamole in the MMTV-PyMT Transgenic Mouse Model of Breast Cancer
Authors: Wang Chunmei , Schwab Luciana P. , Fan Meiyun , Seagroves Tiffany N. , Buolamwini John K.
Published: March 2024

Abstract
Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter-driven polyoma middle T oncoprotein metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics, and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and miRNA expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChip or miRNA 2.0 arrays. Real-time quantitative PCR was used to confirm changes in gene expression. Treatment with DPM beginning at the age of 4 weeks delayed the onset of palpable lesions, delayed tumor progression, and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPM's chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention. Cancer Prev Res; 6(5); 437–47. ©2013 AACR.
Data from American Ginseng Suppresses Colitis through p53-Mediated Apoptosis of Inflammatory Cells
Authors: Jin Yu , Hofseth Anne B. , Cui Xiangli , Windust Anthony J. , Poudyal Deepak , Chumanevich Alex A. , Matesic Lydia E. , Singh Narendra P. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Hofseth Lorne J.
Published: March 2024

Abstract
Ulcerative colitis is a dynamic, chronic inflammatory condition associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism regulating ulcerative colitis. American ginseng (AG) is a putative antioxidant that can suppress hyperactive immune cells. We have recently shown that AG can prevent and treat mouse colitis. Because p53 levels are elevated in inflammatory cells in both mouse and human colitis, we tested the hypothesis that AG protects from colitis by driving inflammatory cell apoptosis through a p53 mechanism. We used isogenic p53+/+ and p53−/− inflammatory cell lines as well as primary CD4+/CD25− effector T cells from p53+/+ and p53−/− mice to show that AG drives apoptosis in a p53-dependent manner. Moreover, we used a dextran sulfate sodium (DSS) model of colitis in C57BL/6 p53+/+ and p53−/− mice to test whether the protective effect of AG against colitis is p53 dependent. Data indicate that AG induces apoptosis in p53+/+ but not in isogenic p53−/− cells in vitro. In vivo, C57BL/6 p53+/+ mice are responsive to the protective effects of AG against DSS-induced colitis, whereas AG fails to protect from colitis in p53−/− mice. Furthermore, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling of inflammatory cells within the colonic mesenteric lymph nodes is elevated in p53+/+ mice consuming DSS + AG but not in p53−/− mice consuming DSS + AG. Results are consistent with our in vitro data and with the hypothesis that AG drives inflammatory cell apoptosis in vivo, providing a mechanism by which AG protects from colitis in this DSS mouse model. Cancer Prev Res; 3(3); 339–47
Data from Direct Targeting of MEK1/2 and RSK2 by Silybin Induces Cell-Cycle Arrest and Inhibits Melanoma Cell Growth
Authors: Lee Mee-Hyun , Huang Zunnan , Kim Dong Joon , Kim Sung-Hyun , Kim Myoung Ok , Lee Sung-Young , Xie Hua , Park Si Jun , Kim Jae Young , Kundu Joydeb Kumar , Bode Ann M. , Surh Young-Joon , Dong Zigang
Published: March 2024

Abstract
Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-κB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell-cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. Cancer Prev Res; 6(5); 455–65. ©2013 AACR.
Data from Cyclic AMP-Responsive Element Binding Protein– and Nuclear Factor-κB–Regulated CXC Chemokine Gene Expression in Lung Carcinogenesis
Authors: Sun Hongxia , Chung Wen-Cheng , Ryu Seung-Hee , Ju Zhenlin , Tran Hai T. , Kim Edward , Kurie Jonathan M. , Koo Ja Seok
Published: March 2024

Abstract
The recognition of the importance of angiogenesis in tumor progression has led to the development of antiangiogenesis as a new strategy for cancer treatment and prevention. By modulating tumor microenvironment and inducing angiogenesis, the proinflammatory cytokine interleukine (IL)-1β has been reported to promote tumor development. However, the factors mediating IL-1β–induced angiogenesis in non–small cell lung cancer (NSCLC) and the regulation of these angiogenic factors by IL-1β are less clear. Here, we report that IL-1β up-regulated an array of proangiogenic CXC chemokine genes in the NSCLC cell line A549 and in normal human tracheobronchial epithelium cells, as determined by microarray analysis. Further analysis revealed that IL-1β induced much higher protein levels of CXC chemokines in NSCLC cells than in normal human tracheobronchial epithelium cells. Conditioned medium from IL-1β–treated A549 cells markedly increased endothelial cell migration, which was suppressed by neutralizing antibodies against CXCL5 and CXCR2. We also found that IL-1β–induced CXC chemokine gene overexpression in NSCLC cells was abrogated with the knockdown of cyclic AMP-responsive element binding protein (CREB) or nuclear factor κB (NF-κB). Moreover, the expression of the CXC chemokine genes as well as CREB and NF-κB activities was greatly increased in the tumorigenic NSCLC cell line compared with normal, premalignant immortalized or nontumorigenic cell lines. A disruptor of the interaction between CREB-binding protein and transcription factors such as CREB and NF-κB, 2-naphthol-AS-E-phosphate (KG-501), inhibited IL-1β–induced CXC chemokine gene expression and angiogenic activity in NSCLC. We propose that targeting CREB or NF-κB using small-molecule inhibitors, such as KG-501, holds promise as a preventive and/or therapeutic approach for NSCLC.
Data from Viewing the Epigenetics of Colorectal Cancer through the Window of Folic Acid Effects
Authors: van Engeland Manon , Herman James G.
Published: March 2024

Abstract
In this issue of the journal (beginning on page 1552), Wallace and colleagues shed new light on the epigenetics of colorectal cancer by exploring the role of changes in DNA methylation in normal-appearing colon biopsies collected during a chemoprevention trial of folic acid. This study and the parent clinical trial will potentially further elucidate the long-studied role of folate in colon cancer development. In particular, the focus on the intermediate biomarker DNA methylation could provide a mechanistic link between folate exposure and colon cancer. Dietary or supplemental folate has complex interactions with important processes that may alter colon cancer development or progression, but this influence is likely altered by supplementation's timing and duration and whether in the setting of depleted or more typical, higher levels of folate. Despite decades of epidemiologic, molecular, and animal studies, answers to what effects these interactions have are complex, often contradictory. This perspective will place this study in context, looking at what it tells us and what it does not. Cancer Prev Res; 3(12); 1509–12. ©2010 AACR.
Data from All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis
Authors: Syed Zanobia , Cheepala Satish B. , Gill Jennifer N. , Stein Jennica , Nathan Cherie Ann , DiGiovanni John , Batra Vinita , Adegboyega Patrick , Kleiner Heather E. , Clifford John L.
Published: March 2024

Abstract
Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate–induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol-13-acetate–treated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B-Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation.
Data from The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition
Authors: McConkey David J. , Dinney Colin P.
Published: March 2024

Abstract
This perspective on Seager et al. (beginning on p. 1008) considers an important advance in the effort to control bladder cancer. Frontline therapy for superficial transitional cell carcinoma of the bladder involves instillation of the crude immunomodulatory bacterial extract Bacillus Calmette-Guérin directly into the organ. Seager et al. now show that local administration of a chemical inhibitor of mammalian target of rapamycin strongly suppressed growth in a novel preclinical mouse model that develops carcinoma in situ, a particularly problematic form of transitional cell carcinoma of the bladder. The results not only support the clinical evaluation of mammalian target of rapamycin inhibitors in this setting, they open the door for the evaluation of additional molecular local therapies as well.
Data from Effect of Chronic and Intermittent Calorie Restriction on Serum Adiponectin and Leptin and Mammary Tumorigenesis
Authors: Rogozina Olga P. , Bonorden Melissa J.L. , Seppanen Christine N. , Grande Joseph P. , Cleary Margot P.
Published: March 2024

Abstract
The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. Cancer Prev Res; 4(4); 568–81. ©2011 AACR.
Data from Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial
Authors: Cho Nancy L. , Redston Mark , Zauber Ann G. , Carothers Adelaide M. , Hornick Jason , Wilton Andrew , Sontag Stephen , Nishioka Norman , Giardiello Francis M. , Saltzman John R. , Gostout Chris , Eagle Craig J. , Hawk Ernest T. , Bertagnolli Monica M.
Published: March 2024

Abstract
Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor α, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.
Data from Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Authors: Kozu Takahiro , Iinuma Gen , Ohashi Yasuo , Saito Yutaka , Akasu Takayuki , Saito Daizo , Alexander David B. , Iigo Masaaki , Kakizoe Tadao , Tsuda Hiroyuki
Published: March 2024

Abstract
Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps ≤5 mm in diameter and likely to be adenomas. Participants were assigned to receive placebo, 1.5-g bLF, or 3.0-g bLF daily for 12 months. Target adenomatous polyps were monitored by colonoscopy. Ingestion of 3.0-g bLF significantly retarded adenomatous polyp growth in participants 63 years old or younger. Removal of adenomatous colorectal polyps is done as a preventative measure against colorectal cancer; however, polyps can be overlooked, and when detected, polypectomy is not always 100% effective in eradicating a polyp. Our study suggests that daily intake of 3.0 g of bLF could be a clinically beneficial adjunct to colorectal polyp extraction.
Data from Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice
Authors: Johnson Thomas E. , Kassie Fekadu , O'Sullivan M. Gerard , Negia Mesfin , Hanson Timothy E. , Upadhyaya Pramod , Ruvolo Peter P. , Hecht Stephen S. , Xing Chengguo
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)–induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor κBNF-κB, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.
Data from A Pilot Surrogate Endpoint Biomarker Study of Celecoxib in Oral Premalignant Lesions
Authors: Wirth Lori J. , Krane Jeffrey F. , Li Yi , Othus Megan , Moran Amy E. , Dorfman David M. , Norris Charles M. , Goguen Laura , Posner Marshall R. , Haddad Robert I. , Bertagnolli Monica M.
Published: March 2024

Abstract
This study evaluated changes in prostaglandin E2 (PGE2) levels and related biomarkers in oral premalignant lesions (OPL) in response to celecoxib treatment. Twenty-two subjects were enrolled and treated with celecoxib. Pretreatment and 12-week biopsies were done. Subjects whose biopsy showed ≥30% decrease in PGE2 remained on celecoxib for a total of 12 months when repeat biopsy was done. Biopsies were examined to assess degree of dysplasia, DNA ploidy, and immunohistochemical expression of BCL2, pAKT-Ser473, Ki-67, and CD31 (microvessel density). In 18 paired biopsies available at baseline and 12 weeks, mean normalized PGE2 levels decreased by 38% (P = 0.002). After 12 months, PGE2 decreased by 31% (P = 0.340). Twelve biopsies (67%; P = 0.0129) showed improvement in degree of dysplasia after 12 weeks, and 8 of 11 biopsies (73%; P = 0.0703) continued to show an improvement in the degree of dysplasia after 12 months. Trends suggested down-modulation of cyclooxygenase-2 and Ki-67 in some tissues, increased pAKT-Ser473 expression, and an inverse relationship between PGE2 and BCL2 expression. This study documents the feasibility of measuring potential surrogate endpoint biomarkers of chemopreventive agent response in OPLs. Treatment with celecoxib in subjects with OPLs favorably modulates the primary mediator of cyclooxygenase-2 activity, PGE2, after 12 weeks.
Data from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
Authors: Bertagnolli Monica M. , Eagle Craig J. , Zauber Ann G. , Redston Mark , Breazna Aurora , Kim KyungMann , Tang Jie , Rosenstein Rebecca B. , Umar Asad , Bagheri Donya , Collins Neal T. , Burn John , Chung Daniel C. , Dewar Thomas , Foley T. Raymond , Hoffman Neville , Macrae Finlay , Pruitt Ronald E. , Saltzman John R. , Salzberg Bruce , Sylwestrowicz Thomas , Hawk Ernest T.
Published: March 2024

Abstract
The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.
Data from Nano-Architectural Alterations in Mucus Layer Fecal Colonocytes in Field Carcinogenesis: Potential for Screening
Authors: Roy Hemant K. , Damania Dhwanil P. , DelaCruz Mart , Kunte Dhananjay P. , Subramanian Hariharan , Crawford Susan E. , Tiwari Ashish K. , Wali Ramesh K. , Backman Vadim
Published: March 2024

Abstract
Current fecal tests (occult blood, methylation, DNA mutations) target minute amounts of tumor products among a large amount of fecal material and thus have suboptimal performance. Our group has focused on exploiting field carcinogenesis as a modality to amplify the neoplastic signal. Specifically, we have shown that endoscopically normal rectal brushings have striking nano-architectural alterations which are detectable using a novel optical technique, partial wave spectroscopic microscopy (PWS). We therefore wished to translate this approach to a fecal assay. We examined mucus layer fecal colonocytes (MLFC) at preneoplastic and neoplastic time points (confirmed with rat colonoscopy) in the azoxymethane (AOM)-treated rat model and conducted PWS analysis to derive the nano-architectural parameter, disorder strength (Ld). We confirmed these results with studies in a genetic model (the Pirc rat). We showed that MLFC appeared microscopically normal, consistent with field carcinogenesis. Ld was elevated at an early time point (5 weeks post-AOM injection, effect size = 0.40, P = 0.024) and plateaued before adenoma formation (10 weeks post-AOM, effect size = 0.66, P = 0.001), with no dramatic increase once tumors developed. We replicated these data in the preneoplastic Pirc rat with an effect size in the MLFC that replicated the rectal brushings (increase vs. age-matched controls of 62% vs. 74%, respectively). We provide the first demonstration of a biophotonics approach to fecal assay. Furthermore, targeting the nano-architectural changes of field carcinogenesis rather than the detection of tumor products may provide a novel paradigm for colorectal cancer screening. Cancer Prev Res; 6(10); 1111–9. ©2013 AACR.
Data from Intervening to Reduce the Future Burden of Occupational Cancer in Britain: What Could Work?
Authors: Hutchings Sally , Cherrie John W. , Van Tongeren Martie , Rushton Lesley
Published: March 2024

Abstract
In Britain, 14 carcinogenic agents and occupational circumstances currently account for 86% of estimated occupation attributable cancer. The future burden associated with these carcinogens has been forecast, using attributable fractions for forecast scenarios representing patterns of past and predicted future exposure, and exposure levels representing the introduction of new occupational exposure limits, increased levels of compliance with these limits and other reductions in worker exposure. Without intervention, occupational attributable cancers are forecast to remain at more than 10,000 by 2060. With modest intervention over 2,600, or with stricter interventions more than 8,200 cancers could be avoided by 2060 although because of long latency no impact will be seen until at least 10 years after intervention. Effective interventions assessed in this study include reducing workplace exposure limits and improving compliance with these limits. Cancers associated with asbestos, diesel engine exhaust, polycyclic aromatic hydrocarbons, work as a painter, radon, and solar radiation are forecast to continue, with construction remaining the prime industry of concern. Although exposure levels to the established carcinogens are falling, workers are remaining exposed at low levels at which there is still a cancer risk, although the aging population also contributes to rising cancer numbers, These forecasts can be used to assess the relative costs to society of different occupational carcinogenic agents, and the relative merits and savings associated with alternative intervention strategies. The methods are adaptable for different data circumstances, other types of interventions and could be extended to environmental carcinogens and other chronic diseases. Cancer Prev Res; 5(10); 1213–22. ©2012 AACR.
Data from Chemoprevention of Intestinal Polyps in ApcMin/+ Mice Fed with Western or Balanced Diets by Drinking Annurca Apple Polyphenol Extract
Authors: Fini Lucia , Piazzi Giulia , Daoud Yahya , Selgrad Michael , Maegawa Shinji , Garcia Melissa , Fogliano Vincenzo , Romano Marco , Graziani Giulia , Vitaglione Paola , Carmack Susanne W. , Gasbarrini Antonio , Genta Robert M. , Issa Jean-Pierre , Boland C. Richard , Ricciardiello Luigi
Published: March 2024

Abstract
The Western diet (WD) is associated with a higher incidence of colorectal cancer (CRC) than the Mediterranean diet. Polyphenols extracted from Annurca apple showed chemopreventive properties in CRC cells. A multifactorial, four-arm study by using wild-type (wt) and ApcMin/+ mice was carried out to evaluate the effect on polyp number and growth of APE treatment (60 μmol/L) ad libitum in drinking water combined with a WD or a balanced diet (BD) for 12 weeks. Compared with APE treatment, we found a significant drop in body weight (P < 0.0001), severe rectal bleeding (P = 0.0076), presence of extraintestinal tumors, and poorer activity status (P = 0.0034) in water-drinking ApcMin/+ mice, more remarkably in the WD arm. In the BD and WD groups, APE reduced polyp number (35% and 42%, respectively, P < 0.001) and growth (60% and 52%, respectively, P < 0.0001) in both colon and small intestine. Increased antioxidant activity was found in wt animals fed both diets and in ApcMin/+ mice fed WD and drinking APE. Reduced lipid peroxidation was found in ApcMin/+ mice drinking APE fed both diets and in wt mice fed WD. In normal mucosa, mice drinking water had lower global levels of DNA methylation than mice drinking APE. APE treatment is highly effective in reducing polyps in ApcMin/+ mice and supports the concept that a mixture of phytochemicals, as they are naturally present in foods, represent a plausible chemopreventive agent for CRC, particularly in populations at high risk for colorectal neoplasia. Cancer Prev Res; 4(6); 907–15. ©2011 AACR.
Data from Ultrasensitive Detection of Unknown Colon Cancer-Initiating Mutations Using the Example of the Adenomatous Polyposis Coli Gene
Authors: Gerecke Christian , Mascher Conny , Gottschalk Uwe , Kleuser Burkhard , Scholtka Bettina
Published: March 2024

Abstract
Detection of cancer precursors contributes to cancer prevention, for example, in the case of colorectal cancer. To record more patients early, ultrasensitive methods are required for the purpose of noninvasive precursor detection in body fluids. Our aim was to develop a method for enrichment and detection of known as well as unknown driver mutations in the Adenomatous polyposis coli (APC) gene. By coupled wild-type blocking (WTB) PCR and high-resolution melting (HRM), referred to as WTB-HRM, a minimum detection limit of 0.01% mutant in excess wild-type was achieved according to as little as 1 pg mutated DNA in the assay. The technique was applied to 80 tissue samples from patients with colorectal cancer (n = 17), adenomas (n = 50), serrated lesions (n = 8), and normal mucosa (n = 5). Any kind of known and unknown APC mutations (deletions, insertions, and base exchanges) being situated inside the mutation cluster region was distinguishable from wild-type DNA. Furthermore, by WTB-HRM, nearly twice as many carcinomas and 1.5 times more precursor lesions were identified to be mutated in APC, as compared with direct sequencing. By analyzing 31 associated stool DNA specimens all but one of the APC mutations could be recovered. Transferability of the WTB-HRM method to other genes was proven using the example of KRAS mutation analysis. In summary, WTB-HRM is a new approach for ultrasensitive detection of cancer-initiating mutations. In this sense, it appears especially applicable for noninvasive detection of colon cancer precursors in body fluids with excess wild-type DNA like stool. Cancer Prev Res; 6(9); 898–907. ©2013 AACR.
Data from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers
Authors: Park Il-Seok , Chang Xiaofei , Loyo Myriam , Wu Gaosong , Chuang Alice , Kim Myoung Sook , Chae Young Kwang , Lyford-Pike Sofia , Westra William H. , Saunders John R. , Sidransky David , Pai Sara Isabel
Published: March 2024

Abstract
Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16–associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers. Cancer Prev Res; 4(2); 207–17. ©2011 AACR.
Data from Raloxifene and Antiestrogenic Gonadorelin Inhibits Intestinal Tumorigenesis by Modulating Immune Cells and Decreasing Stem-like Cells
Authors: Janakiram Naveena B. , Mohammed Altaf , Brewer Misty , Bryant Taylor , Biddick Laura , Lightfoot Stan , Pathuri Gopal , Gali Hariprasad , Rao Chinthalapally V.
Published: March 2024

Abstract
Studies suggest that estrogen plays a contributing role in colorectal cancer. This project examined the preventive effects of raloxifene, a selective estrogen receptor modulator (SERM), and gonadorelin, an antiestrogenic drug, in female ApcMin/+ mouse intestinal tumorigenesis. Six-week-old ApcMin/+mice were fed diet containing 1 ppm raloxifene or control diet. Gonadorelin (150 ng/mouse) was injected subcutaneously into one treatment group. Intestinal tumors were evaluated for tumor multiplicity and size. Mice treated with raloxifene and gonadorelin showed colon tumor inhibition of 80% and 75%, respectively. Both drugs significantly inhibited small intestinal tumor multiplicity and size (75%–65%, P < 0.0001). Raloxifene and gonadorelin showed significant tumor inhibition with 98% and 94% inhibition of polyps >2 mm in size. In mice fed with raloxifene or injected with gonadorelin, tumors showed significantly reduced proliferating cell nuclear antigen expression (58%–65%, P < 0.0001). Raloxifene treatment decreased β-catenin, cyclin D1, laminin 1β, Ccl6, and stem-like cells (Lgr 5, EpCAM, CD44/CD24), as well as suppressed inflammatory genes (COX-2, mPGES-1, 5-LOX,). Gonadorelin showed significant decrease in COX-2, mPGES-1, iNOS, and stem-like cells or increased NK cells and chemokines required for NK cells. Both drugs were effective in suppressing tumor growth albeit with different mechanisms. These observations show that either suppression of estrogen levels or modulation of estrogen receptor dramatically suppresses small intestinal and colonic tumor formation in female ApcMin/+ mice. These results support the concept of chemoprevention by these agents in reducing endogenous levels of estrogen or modulating ER signaling. Cancer Prev Res; 7(3); 300–9. ©2014 AACR.
Data from Organ Specificity of the Bladder Carcinogen 4-Aminobiphenyl in Inducing DNA Damage and Mutation in Mice
Authors: Yoon Jae-In , Kim Sang-In , Tommasi Stella , Besaratinia Ahmad
Published: March 2024

Abstract
Aromatic amines are a widespread class of environmental contaminants present in various occupational settings and tobacco smoke. Exposure to aromatic amines is a major risk factor for bladder cancer development. The etiologic involvement of aromatic amines in the genesis of bladder cancer is attributable to their ability to form DNA adducts, which upon eluding repair and causing mispairing during replication, may initiate mutagenesis. We have investigated the induction of DNA adducts in relation to mutagenesis in bladder and various nontarget organs of transgenic Big Blue mice treated weekly (i.p.) with a representative aromatic amine compound, 4-aminobiphenyl (4-ABP), for six weeks, followed by a six-week recovery period. We show an organ-specificity of 4-ABP in inducing repair-resistant DNA adducts in bladder, kidney, and liver of carcinogen-treated animals, which accords with the bioactivation pathway of this chemical in the respective organs. In confirmation, we show a predominant and sustained mutagenic effect of 4-ABP in bladder, and much weaker but significant mutagenicity of 4-ABP in the kidney and liver of carcinogen-treated mice, as reflected by the elevation of background cII mutant frequency in the respective organs. The spectrum of mutations produced in bladder of 4-ABP–treated mice matches the known mutagenic properties of 4-ABP–DNA adducts, as verified by the preponderance of induced mutations occurring at G:C base pairs (82.9%), with the vast majority being G:C→T:A transversions (47.1%). Our data support a possible etiologic role of 4-ABP in bladder carcinogenesis and provide a mechanistic view on how DNA adduct–driven mutagenesis, specifically targeted to bladder urothelium, may account for organ-specific tumorigenicity of this chemical. Cancer Prev Res; 5(2); 299–308. ©2011 AACR.