bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of the WNT Target and Cancer Stem Cell Marker CD44 in Apc(Min/+) Mice Attenuates Intestinal Tumorigenesis
Authors: Zeilstra Jurrit , Joosten Sander P.J. , Dokter Maarten , Verwiel Eugène , Spaargaren Marcel , Pals Steven T.
Published: May 2008

Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active β-catenin/TCF–mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts. The expression of CD44 is dramatically increased in aberrant crypt foci in both humans and tumor-susceptible ApcMin/+ mice, suggesting a role for CD44 in intestinal tumorigenesis. To study this role, we crossed C57BL/6J-Cd44−/− mice with C57BL/6J-ApcMin/+ mice. Compared with C57BL/6J-Cd44+/+/ApcMin/+ mice, C57BL/6J-Cd44−/−/ApcMin/+ mice showed an almost 50% reduction in the number of intestinal adenomas. This reduction was primarily caused by a decrease in the formation of aberrant crypts, implying the involvement of CD44 in tumor initiation. The absence of CD44 in the normal (nonneoplastic) crypts of Cd44−/−/ApcMin/+ mice did not alter the proliferative capacity and size of the intestinal stem cell and transit-amplifying compartments. However, compared with Cd44+/+/ApcMin/+ mice, Cd44−/−/ApcMin/+ showed an increase in the number of apoptotic epithelial cells at the base of the crypt which correlated with an increased expression of the proapoptotic genes Bok and Dr6. Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt. [Cancer Res 2008;68(10):3655–61]
Protein Kinase D3 (PKD3) Contributes to Prostate Cancer Cell Growth and Survival Through a PKCε/PKD3 Pathway Downstream of Akt and ERK 1/2
Authors: Chen Jun , Deng Fan , Singh Shivendra V. , Wang Qiming J.
Published: May 2008

Protein kinase D (PKD) is a family of novel diacylglycerol/phorbol ester targets that regulate many important cellular functions including cell growth and survival. We now provide experimental evidence to indicate that PKD3 contributes to prostate cancer cell growth and survival. Expression of PKD3 as well as PKD1 was significantly higher in human prostate tumors compared with normal tissues as revealed by immunohistochemistry. Moreover, PKD3 exhibited a marked increase in nuclear localization in tumor tissues, which correlated with tumor grade. Isoforms of PKD were differentially expressed and localized between normal and human prostate cancer cells. Increased protein expression and nuclear accumulation of PKD3 were observed in the more aggressive androgen-independent PC3 and DU145 cells compared with the less aggressive androgen-dependent LNCaP cells. Overexpression of wild-type PKD3 in LNCaP cells blocked phorbol 12-myristate 13-acetate (PMA)-induced apoptosis in association with inhibition of PMA-induced down-regulation of Akt activity, and prolonged extracellular signal-regulated kinase (ERK)1/2 activation. Overexpression of wild-type PKD3 also promoted S phase entry, whereas depletion of endogenous PKD3 resulted in G0-G1 phase cell cycle arrest and inhibition of PC3 cell proliferation. In PC3 and DU145 cells, PKCε regulated PKD3 kinase activity and nuclear localization. Moreover, ectopical expression of PKD3 increased, whereas depletion of endogenous PKD3 reduced basal Akt and ERK1/2 activities. Further analysis showed that up-regulation of Akt activity induced by PKD3 required phosphatidylinositol-3-OH kinase and p38. In summary, our data indicate that PKD3 contributes to growth and survival of prostate cancer cells and may represent a novel therapeutic target for prostate cancer. [Cancer Res 2008;68(10):3844–53]
Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment
Authors: Augustine Christina K. , Yoshimoto Yasunori , Gupta Mukur , Zipfel Patricia A. , Selim M. Angelica , Febbo Phillip , Pendergast Ann Marie , Peters William P. , Tyler Douglas S.
Published: May 2008

Malignant transformation in melanoma is characterized by a phenotype “switch” from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin–expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma. [Cancer Res 2008;68(10):3777–84]
Inhibition of Photocarcinogenesis by Platelet-Activating Factor or Serotonin Receptor Antagonists
Authors: Sreevidya Coimbatore S. , Khaskhely Noor M. , Fukunaga Atsushi , Khaskina Polina , Ullrich Stephen E.
Published: May 2008

The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT2A) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT2A to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT2A receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT2A receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT2A receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT2A receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression. [Cancer Res 2008;68(10):3978–84]
UVA-Induced Cell Cycle Progression Is Mediated by a Disintegrin and Metalloprotease/Epidermal Growth Factor Receptor/AKT/Cyclin D1 Pathways in Keratinocytes
Authors: He Yu-Ying , Council Sarah E. , Feng Li , Chignell Colin F.
Published: May 2008

UVA (315–400 nm), which constitutes ∼95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer. [Cancer Res 2008;68(10):3752–8]
Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors
Authors: Nagano Satoshi , Perentes Jean Yannis , Jain Rakesh K. , Boucher Yves
Published: May 2008

The success of tumor oncolytic virotherapy is limited by the poor penetration of virus in tumors. Interstitial collagen fibers and the narrow spacing between cancer cells are major barriers hindering the movement of large viral particles. To bypass the cellular barrier, we tested the hypothesis that the void space produced by cancer cell apoptosis enhances the initial spread and efficacy of oncolytic herpes simplex virus (HSV). In mice with mammary tumors, apoptosis was induced by doxycycline-regulated expression/activation of CD8/caspase-8, paclitaxel, or paclitaxel plus tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). In both collagen-poor and collagen-rich tumors, apoptosis or necrosis increased the initial intratumoral spread of HSV. Compared with the isolated pattern of HSV infection generally located in the center of control tumors, apoptosis induction and a single i.t. injection of virus produced an interconnected and diffuse pattern of infection, which extended from the tumor center to the periphery. This interconnected pattern of viral infection correlated with the formation of void spaces and channel-like structures in apoptosis-rich tumor areas. We also show that the i.t. injection of HSV after caspase-8 activation or paclitaxel-TRAIL pretreatment retards tumor growth, whereas HSV administration before tumor cell death induction did not improve therapeutic efficacy. Hence, our findings show that the induction of cancer cell death before the injection of oncolytic HSV enhances intratumoral virus delivery/penetration and antitumor efficacy. [Cancer Res 2008;68(10):3795–802]
Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities
Authors: Natsume Akito , In Mika , Takamura Hiroyuki , Nakagawa Tomoaki , Shimizu Yukiko , Kitajima Kazuko , Wakitani Masako , Ohta So , Satoh Mitsuo , Shitara Kenya , Niwa Rinpei
Published: May 2008

Enhancement of multiple effector functions of an antibody may be a promising approach for antibody therapy. We have previously reported that fucose removal from Fc-linked oligosaccharides greatly enhances antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies. Here, we report a unique approach to enhance complement-dependent cytotoxicity (CDC), another important effector function of antitumor antibodies, by using engineered constant region of human IgG1/IgG3 chimeric isotypes. We systematically shuffled constant domains of IgG1 and IgG3 to generate a comprehensive set of mixed chimeric isotypes of anti-CD20 antibodies. Among these, the variant 1133, consisting of the CH1 and the hinge each from IgG1 and the Fc from IgG3, was unexpectedly found to exhibit markedly enhanced CDC that exceeded wild-type levels. However, it lacked protein A–binding capacity, an important feature for the industrial production. To eliminate this deficiency, a portion in COOH-terminal CH3 domain of 1133 was substituted with IgG1, resulting in full recovery of protein A binding without compromising the enhanced CDC and ADCC activities. The CDC-enhancing effect using a chimeric isotype was also shown in CD52 antigen/antibody system. The ADCC activity of the variants was also maximized by the absence of fucose from its carbohydrate structure, a phenomenon that has previously been observed for wild-type antibodies. Enhanced cytotoxicity of a variant was confirmed in a cynomolgus monkey model. These findings suggest that the variant antibodies with IgG1/IgG3 chimeric constant regions and nonfucosylated oligosaccharides that possess dual-enhanced cytotoxic functions may be an improvement for the next generation of therapeutic antitumor antibodies. [Cancer Res 2008;68(10):3863–72]
Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells
Authors: Contessa Joseph N. , Bhojani Mahaveer S. , Freeze Hudson H. , Rehemtulla Alnawaz , Lawrence Theodore S.
Published: May 2008

Receptor tyrosine kinases (RTK) are therapeutic targets for the treatment of malignancy. However, tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades. Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell. We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling. Using the N-linked glycosylation inhibitor, tunicamycin, we show that expression levels of several RTKS (EGFR, ErbB2, ErbB3, and IGF-IR) are exquisitely sensitive to inhibition of N-linked glycosylation. Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments. Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines, two cell lines resistant to epidermal growth factor receptor–targeted therapies, we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells. In comparison, experiments in nontransformed cells showed neither a reduction in RTK-dependent signaling nor an enhancement in radiosensitivity, suggesting the potential for a therapeutic ratio between tumors and normal tissues. This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies. [Cancer Res 2008;68(10):3803–9]
Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells
Authors: Svenson Ulrika , Nordfjäll Katarina , Stegmayr Birgitta , Manjer Jonas , Nilsson Peter , Tavelin Björn , Henriksson Roger , Lenner Per , Roos Göran
Published: May 2008

Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09–8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (≤median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33–6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease. [Cancer Res 2008;68(10):3618–23]
LKB1 and Lung Cancer: More Than the Usual Suspects
Authors: Shah Usman , Sharpless Norman E. , Hayes D. Neil
Published: May 2008

Often, the problem in cancer research is figuring out how a gene or pathway works in regulating cellular transformation. The question of what RAS activates or PTEN inhibits have been classic dilemmas of modern cancer biology. In these cases, biochemical and genetic studies have provided us with a fairly clear picture of the cancer relevant functions of these genes. For LKB1, a more recently identified human tumor suppressor gene, however, the problem is different. This serine-threonine kinase that is conserved from yeast to mammals seems to play a role in many diverse cellular pathways. Therefore, although elegant functional and genetic approaches have established critical roles for LKB1 in the regulation of metabolism, motility, polarity, and the cell cycle, the role(s) responsible for its true tumor suppressor function(s) is unknown. One is reminded of an Agatha Christie murder mystery where nearly every character in the book has reason to be suspected of committing the crime—there are too many suspects for how LKB1 might repress lung cancer. [Cancer Res 2008;68(10):3562–5]
Association of γ-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study
Authors: Strasak Alexander M. , Rapp Kilian , Brant Larry J. , Hilbe Wolfgang , Gregory Martin , Oberaigner Willi , Ruttmann Elfriede , Concin Hans , Diem Günter , Pfeiffer Karl P. , Ulmer Hanno ,   and the VHM&PP Study Group
Published: May 2008

Although several epidemiologic studies have shown that γ-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages ≤65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men. [Cancer Res 2008;68(10):3970–7]
The Nuclear Receptor Coactivator Amplified in Breast Cancer-1 Is Required for Neu (ErbB2/HER2) Activation, Signaling, and Mammary Tumorigenesis in Mice
Authors: Fereshteh Mark P. , Tilli Maddalena T. , Kim Sung Eun , Xu Jianming , O'Malley Bert W. , Wellstein Anton , Furth Priscilla A. , Riegel Anna T.
Published: May 2008

Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3+/− mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3wt mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH2 kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3+/− tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer. [Cancer Res 2008;68(10):3697–706]
Genetic Ablation of M3 Muscarinic Receptors Attenuates Murine Colon Epithelial Cell Proliferation and Neoplasia
Authors: Raufman Jean-Pierre , Samimi Roxana , Shah Nirish , Khurana Sandeep , Shant Jasleen , Drachenberg Cinthia , Xie Guofeng , Wess Jürgen , Cheng Kunrong
Published: May 2008

Colon epithelial cells express and most colon cancers overexpress M3 muscarinic receptors (M3R). In human colon cancer cells, post-M3R signaling stimulates proliferation. To explore the importance of M3R expression in vivo, we used the azoxymethane-induced colon neoplasia model. Mice treated with weekly i.p. injection of saline [10 wild-type (WT) mice] or azoxymethane (22 WT and 16 M3R−/− mice) for 6 weeks were euthanized at 20 weeks. At week 20, azoxymethane-treated WT mice weighed ∼16% more than M3R−/− mice (33.4 grams ± 1.0 grams versus 27.9 grams ± 0.5 grams; mean ± SE, P < 0.001). In azoxymethane-treated M3R−/− mice, cell proliferation (BrdUrd staining) was reduced 43% compared with azoxymethane-treated WT mice (P < 0.05). Whereas control mice (both WT and M3R−/−) had no colon tumors, azoxymethane-treated WT mice had 5.3 ± 0.5 tumors per animal. Strikingly, azoxymethane-treated M3R−/− mice had only 3.2 ± 0.3 tumors per mouse (P < 0.05), a 40% reduction. Tumor volume in azoxymethane-treated M3R−/− mice was reduced 60% compared with azoxymethane-treated WT mice (8.1 mm3 ± 1.5 mm3 versus 20.3 mm3 ± 4.1 mm3; P < 0.05). Compared with WT, fewer M3R−/− mice had adenomas (6% versus 36%; P = 0.05), and M3R−/− mice had fewer adenocarcinomas per mouse (0.6 ± 0.1 versus 1.7 ± 0.4; P < 0.05). Eleven of 22 WT but no M3R−/− mice had multiple adenocarcinomas (P < 0.001). Compared with WT, azoxymethane-treated M3R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M3R and post-M3R signaling are novel therapeutic targets for colon cancer. [Cancer Res 2008;68(10):3573–8]
Ikaros Modulates Cholesterol Uptake: A Link between Tumor Suppression and Differentiation
Authors: Loeper Siobhan , Asa Sylvia L. , Ezzat Shereen
Published: May 2008

Ikaros is a transcription factor that directs lymphoid lineage commitment and pituitary neuroendocrine cell expansion and function. Here, we show that Ikaros regulates the low-density lipoprotein receptor (LDL-R) to alter metabolism in pituitary corticotroph cells. The DNA-binding Ikaros isoform Ik1 binds and enhances activity of the LDL-R promoter. Ik1 decreases methylation and increases acetylation of histone H3 (Lys9) at the LDL-R promoter. Confocal microscopy and quantitative fluorometry show enhanced LDL endocytosis in Ik1-transfected cells that exhibit abundant endoplasmic reticulum, large Golgi complexes, and prominent secretory granule formation, consistent with more robust cholesterol incorporation into functionally relevant membrane-rich organelles. Consistent with these data, LDL-R−/− mice, like Ik−/− mice, have decreased circulating levels of adrenocorticotropic hormone. These findings expand the repertoire of Ikaros actions to include regulation of the cholesterol uptake metabolic pathway with therapeutic implications for lipid-modifying drugs in Ikaros-associated cancers. [Cancer Res 2008;68(10):3715–23]
Secretable Chaperone Grp170 Enhances Therapeutic Activity of a Novel Tumor Suppressor, mda-7/IL-24
Authors: Gao Ping , Sun Xiaolei , Chen Xing , Wang Yanping , Foster Barbara A. , Subjeck John , Fisher Paul B. , Wang Xiang-Yang
Published: May 2008

Melanoma differentiation–associated gene-7 (mda-7)/interleukin-24 (IL-24) is a cancer-specific, apoptosis-inducing gene with broad-spectrum antitumor activity, making it an ideal candidate for a novel cancer gene therapy. A systemic and sustained antitumor immune response generated at the time of initial molecular-targeted therapy would provide additional clinical benefits in cancer patients, resulting in improved prevention of tumor recurrence. In this study, we explored the therapeutic efficacy of intratumoral delivery of a nonreplicating adenoviral vector encoding mda-7/IL-24 (Ad.mda-7) and a secretable form of endoplasmic reticulum resident chaperone grp170 (Ad.sgrp170), a potent immunostimulatory adjuvant and antigen carrier. Intratumoral administration of Ad.mda-7 in combination with Ad.sgrp170 was more effective in controlling growth of TRAMP-C2 prostate tumor compared with either Ad.mda-7 or Ad.sgrp170 treatment. Generation of systemic antitumor immunity was shown by enhanced protection against subsequent tumor challenge and improved control of distant tumors. The combined treatments enhanced antigen and tumor-specific T-cell response, as indicated by increased IFN-γ production and cytolytic activity. Antibody depletion suggests that CD8+ T cells may be involved in the antitumor effect of the dual molecule–targeted therapies. Therefore, introducing immunostimulatory chaperone grp170 in situ strongly promotes the “immunogenic” cell death when delivered to the mda-7/IL-24–induced apoptotic tumor cells, indicating that an improved anticancer efficacy may be achieved by concurrently targeting both tumor and immune compartments. Given multiple undefined antigens present endogenously within prostate cancer, these data provide a rationale for combining sgrp170-based vaccine strategy with mda-7/IL-24–targeted cancer therapy to induce durable systemic immunity. [Cancer Res 2008;68(10):3890–8]
Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17
Authors: Nam Jeong-Seok , Terabe Masaki , Kang Mi-Jin , Chae Helen , Voong Nga , Yang Yu-an , Laurence Arian , Michalowska Aleksandra , Mamura Mizuko , Lonning Scott , Berzofsky Jay A. , Wakefield Lalage M.
Published: May 2008

Overexpression of the immunosuppressive cytokine transforming growth factor β (TGF-β) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-β. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-β and IL-6 in vitro. Treatment of mice with anti–TGF-β antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-β may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17–dependent mechanism. [Cancer Res 2008;68(10):3915–23]
Urinary Metalloproteinases: Noninvasive Biomarkers for Breast Cancer Risk Assessment
Authors: Pories Susan E. , Zurakowski David , Roy Roopali , Lamb Carolyn C. , Raza Sughra , Exarhopoulos Alexis , Scheib Rochelle G. , Schumer Susan , Lenahan Corrine , Borges Virginia , Louis Gwendolyn W. , Anand Ankur , Isakovich Nina , Hirshfield-Bartek Judi , Wewer Ulla , Lotz Margaret M. , Moses Marsha A.
Published: May 2008

Matrix metalloproteinases (MMP) and a disintegrin and metalloprotease 12 (ADAM 12) can be detected in the urine of breast cancer patients and provide independent prediction of disease status. To evaluate the potential of urinary metalloproteinases as biomarkers to predict breast cancer risk status, urine samples from women with known risk marker lesions, atypical hyperplasia and lobular carcinoma in situ (LCIS), were analyzed. Urine samples were obtained from 148 women: 44 women with atypical hyperplasia, 24 women with LCIS, and 80 healthy controls. MMP analysis was done using gelatin zymography and ADAM 12 analysis was done via immunoblotting with monospecific antibodies and subsequent densitometric measurement. Positive urinary MMP-9 levels indicated a 5-fold risk of atypical hyperplasia and >13-fold risk of LCIS compared with normal controls. Urinary ADAM 12 levels were significantly elevated in women with atypical hyperplasia and LCIS from normal controls, with receiver operating characteristic curve analysis showing an area under the curve of 0.914 and 0.950, respectively. To assess clinical applicability, a predictive index was developed using ADAM 12 in conjunction with Gail risk scores for women with atypia. Scores above 2.8 on this ADAM 12-Gail risk prediction index score are predictive of atypical hyperplasia (sensitivity, 0.976; specificity, 0.977). Our data suggest that the noninvasive detection and analysis of urinary ADAM 12 and MMP-9 provide important clinical information for use as biomarkers in the identification of women at increased risk of developing breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1034–12)
Estrogen Receptor–Negative Breast Cancer Is Less Likely to Arise among Lipophilic Statin Users
Authors: Kumar Anjali S. , Benz Christopher C. , Shim Veronica , Minami Christina A. , Moore Dan H. , Esserman Laura J.
Published: May 2008

Background: Preclinical studies have shown the anticancer potential of HMG-CoA reductase enzyme inhibitors (statins), whereas epidemiologic studies remain controversial. Because lipophilic statins show preclinical anticancer activity against hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)]–negative breast cancer models, we explored the hormone receptor phenotype of breast cancers that arise in statin users.

Methods: We did a retrospective cohort analysis via electronic pharmacy records from the Kaiser Permanente Northern California Cancer Registry on 2,141 female patients listed in 2003 as incident cases of breast malignancy. Measures included tumor grade, stage, and receptor phenotype in statin users versus nonusers and controlled for hormone replacement therapy and race.

Results: 387 of the 2,141 breast cancer patients used lipophilic statins [lovastatin (85%), simvastatin, and atorvastatin]. Fifty-one women developed ER/PR-negative tumors. The age-adjusted odds ratio (OR) of developing an ER/PR negative tumor was 0.63 (95% confidence interval, 0.43-0.92; P = 0.02) for statin use ≥1 year before breast cancer diagnosis compared with statin use <1 year (including nonuse). Breast cancers in patients with ≥1 year of statin use were more likely to be low grade (OR, 1.44) and less invasive stage (OR, 1.42).

Conclusions: Breast cancer patients with exposure to statins have proportionately fewer ER/PR-negative tumors that are of lower grade and stage. Although our data set cannot address whether statins affect the incidence of breast cancer, we show that statin use may influence the phenotype of tumors. This suggests a new potential strategy for breast cancer prevention, that of combining statins with agents that prevent ER-positive cancer (tamoxifen, aromatase inhibitors). (Cancer Epidemiol Biomarkers Prev 2008;17(5):1028–33)
Direct Genotyping of Single Nucleotide Polymorphisms in Methyl Metabolism Genes Using Probe-Free High-Resolution Melting Analysis
Authors: Kristensen Lasse S. , Dobrovic Alexander
Published: May 2008

High-resolution melting (HRM) shows great promise for high-throughput, rapid genotyping of individual polymorphic loci. We have developed HRM assays for genotyping single nucleotide polymorphisms (SNP) in several key genes that are involved in methyl metabolism and may directly or indirectly affect the methylation status of the DNA. The SNPs are in the 5,10-methylenetetrahydrofolate reductase (MTHFR; C677T and A1298C), methionine synthetase (MTR; 5-methyltetrahydrofolate-homocysteine methyltransferase; A2756G), and DNA methyltransferase 3b (DNMT3b; C46359T and C31721T) loci. The choice of short amplicons led to greater melting temperature (Tm) differences between the two homozygous genotypes, which allowed accurate genotyping without the use of probes or spiking with control DNA. In the case of MTHFR, there is a second rarer SNP (rs4846051) close to the A1298C SNP that may result in inaccurate genotyping. We masked this second SNP by placing the primer over it and choosing a base at the polymorphic position that was equally mismatched to both alleles. The HRM assays were done on HRM capable real-time PCR machines rather than stand-alone HRM machines. Monitoring the amplification allows ready identification of samples that may give rise to aberrant melting curves because of PCR abnormalities. We show that samples amplifying markedly late can give rise to shifted melting curves without alteration of shapes and potentially lead to misclassification of genotypes. In conclusion, rapid and high-throughput SNP analysis can be done with probe-free HRM if sufficient attention is paid to amplicon design and quality control to omit aberrantly amplifying samples. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1240–7)
Association between Transillumination Breast Spectroscopy and Quantitative Mammographic Features of the Breast
Authors: Blackmore Kristina M. , Knight Julia A. , Lilge Lothar
Published: May 2008

Transillumination breast spectroscopy (TiBS) uses nonionizing optical radiation to gain information about tissue properties directly from the breast. TiBS measurements were obtained from 225 women with normal mammograms. Principal component analysis was used to reduce the spectral data set into four principal components and to generate four TiBS scores (t1-t4) for each woman. These components and scores represent light scattering, water, lipid, and hemoglobin content. Percent density, dense area, and nondense area were measured using Cumulus. The association between TiBS scores and quantitative mammographic features was analyzed using linear regression stratified by menopausal status and adjusted for body mass index. Among premenopausal women, t1 and t3 were significantly associated with percent density (βt1 = −0.14, P = 0.04; βt3 = −2.43, P < 0.0001), whereas t2 and t3 were significantly associated with dense area (βt2 = −1.57, P < 0.0001; βt3 = −2.54, P < 0.0001). Among postmenopausal women, t1, t3, and t4 were significantly associated with percent density (βt1 = −0.30, P < 0.0001; βt3 = −2.51, P < 0.0001; βt4 = 4.75, P < 0.0001) and dense area (βt1 = −0.19, P = 0.004; βt3 = −2.13, P = 0.002; βt4 = 5.02, P < 0.0001). Scores t2 and t4 were also significantly correlated with age among postmenopausal women (rt2 = 0.41 and rt4 = −0.36). Given the association with quantitative mammographic features and tissue changes related to age and menopause, TiBS scores may prove useful as intermediate markers in studies of breast cancer etiology and prevention. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1043–50)
Aberrant Crypt Focus Size Predicts Distal Polyp Histopathology
Authors: Kim Jae , Ng Jennie , Arozulllah Ahsan , Ewing Ronald , Llor Xavier , Carroll Robert E. , Benya Richard V.
Published: May 2008

Aberrant crypt foci (ACF) are the earliest histopathologic lesion associated with colorectal cancer. ACFs are commonly used as a surrogate marker for colorectal cancer chemoprevention studies in rodents and, more recently, in humans. However, ACF prevalence in unselected populations is not known, nor which ACF features are important for predicting polyp histopathology. To address these questions, we did magnification chromo-colonoscopy on all patients undergoing routine colorectal cancer screening over a 31-month period. ACFs were classified by location, size (small, <20 crypts/ACF; medium, 20-100 crypts/ACF; large, >100 crypts/ACF), and whether they were elevated above the tissue plane. Overall, 802 magnification chromo-colonoscopies with ACF enumeration were done. Mean patient age was 58.6 ± 8.5 years, of whom 56% were female, 58% were African American, 21% were Caucasian, and 16% were Latino. Total ACF number, along with increasing ACF size and elevation, correlated with the presence of distal hyperplastic polyps and were higher in African Americans. In contrast, ever-smaller ACFs correlated with the presence of distal adenomas and were independent of age and race. The odds ratio for patients with ≥6 small ACFs and adenomas was 6.02 (95% confidence interval, 2.64-13.70) compared with patients with ≤5 small ACFs, whereas the odds ratio for patients with ≥1 large ACF and hyperplastic polyps was 5.88 (95% confidence interval, 3.00-11.67) compared with patients with none. Small flat ACFs correlate with the presence of distal adenomas, whereas large raised ACFs correlate with the presence of hyperplastic polyps. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1155–62)
Effect Modification by Catalase Genotype Suggests a Role for Oxidative Stress in the Association of Hormone Replacement Therapy with Postmenopausal Breast Cancer Risk
Authors: Quick Sylvia K. , Shields Peter G. , Nie Jing , Platek Mary E. , McCann Susan E. , Hutson Alan D. , Trevisan Maurizio , Vito Dominica , Modali Ramakrishna , Lehman Teresa A. , Seddon Mike , Edge Stephen B. , Marian Catalin , Muti Paola , Freudenheim Jo L.
Published: May 2008

Catalase, a ubiquitous heme enzyme, catalyzes conversion of hydrogen peroxide to water and molecular oxygen, protecting cells from oxidative stress. A C/T polymorphism in the promoter region of the CAT gene (rs1001179) affects transcriptional activity and RBC catalase levels. Oxidative stress may explain the observed increased postmenopausal breast cancer risk associated with hormone replacement therapy (HRT). We examined CAT genotype, HRT, and postmenopausal breast cancer risk in the Western New York Exposures and Breast Cancer case-control study. Cases (n = 616) were women with primary, incident, pathologically confirmed breast cancer. Randomly selected controls (n = 1,082) were frequency matched to cases on age and race. Genotype was assayed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for potential confounders. CAT genotype alone was not associated with breast cancer risk. Ever use of HRT was associated with increased risk (OR, 1.39; 95% CI, 1.11-1.75). The increase with ever use was more pronounced among those with variant CT or TT CAT genotype (OR, 1.88; 95% CI, 1.29-2.75) than among those with CC (OR, 1.15; 95% CI, 0.86-1.54). Similarly, risk associated with ≥5 years of HRT use was greater among those with at least one variant T allele (OR, 2.32; 95% CI, 1.50-3.59). Increased risk was limited to estrogen receptor–positive tumors. Our findings suggest that CAT genotype modifies the effect of HRT use on breast cancer risk and that HRT may affect risk by affecting oxidative stress. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1082–7)
Teeth Loss and Risk of Cancer at 14 Common Sites in Japanese
Authors: Hiraki Akio , Matsuo Keitaro , Suzuki Takeshi , Kawase Takakazu , Tajima Kazuo
Published: May 2008

Background: Tooth loss has been associated with a higher risk of several types of cancer. To clarify the significance of tooth loss to the risk of 14 common cancers, we conducted a large-scale, case-control study based on the Hospital-based Epidemiologic Research Program at Aichi Cancer Center.

Methods: A total of 5,240 cancer subjects and 10,480 age- and sex-matched noncancer controls were recruited. Patients with 14 types of cancer newly diagnosed from 2000 to 2005 were eligible as case subjects, and new outpatients without cancer in the same time period were eligible as controls. Tooth loss was categorized into four groups: group 1, number of remaining teeth, ≥21; group 2, 9 to 20; group 3, 1 to 8; and group 4, 0. The effect of tooth loss was assessed as odds ratios (OR) with 95% confidence intervals (95% CI) calculated with conditional logistic regression models, with adjustment for potential confounders.

Results: A decreased number of remaining teeth was associated with increased OR of head and neck (OR, 1.68; 95% CI, 0.88-1.93; Ptrend = 0.055), esophageal (OR, 2.36; 95% CI, 1.17-4.75; Ptrend = 0.002), and lung (OR, 1.54; 95% CI, 1.05-2.27; Ptrend = 0.027) cancers.

Conclusions: We showed a significant positive association between tooth loss and the risk of head and neck, esophageal, and lung cancers after adjustment for potential confounding factors. The findings indicate that preventive efforts aimed at the preservation of teeth may decrease the risk of these cancers. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1222–7)
A 9-Year Follow-up Study of Participants and Nonparticipants in Sigmoidoscopy Screening: Importance of Self-Selection
Authors: Blom Johannes , Yin Li , Lidén Annika , Dolk Anders , Jeppsson Bengt , Påhlman Lars , Holmberg Lars , Nyrén Olof
Published: May 2008

Background: Self-selection may compromise cost-effectiveness of screening programs. We hypothesized that nonparticipants have generally higher morbidity and mortality than participants.

Methods: A Swedish population-based random sample of 1,986 subjects ages 59 to 61 years was invited to sigmoidoscopy screening and followed up for 9 years by means of multiple record linkages to health and population registers. Gender-adjusted cancer incidence rate ratio (IRR) and overall and disease group-specific and mortality rate ratio (MRR) with 95% confidence intervals (95% CI) were estimated for nonparticipants relative to participants. Cancer and mortality rates were also estimated relative to the age-matched, gender-matched, and calendar period-matched Swedish population using standardized incidence ratios and standardized mortality ratios.

Results: Thirty-nine percent participated. The incidence of colorectal cancer (IRR, 2.2; 95% CI, 0.8-5.9), other gastrointestinal cancer (IRR, 2.7; 95% CI, 0.6-12.8), lung cancer (IRR, 2.2; 95% CI, 0.8-5.9), and smoking-related cancer overall (IRR, 1.4; 95% CI, 0.7-2.5) tended to be increased among nonparticipants relative to participants. Standardized incidence ratios for most of the studied cancers tended to be >1.0 among nonparticipants and <1.0 among participants. Mortality from all causes (MRR, 2.4; 95% CI, 1.7-3.4), neoplastic diseases (MRR, 1.9; 95% CI, 1.1-3.5), gastrointestinal cancer (MRR, 4.7; 95% CI, 1.1-20.7), and circulatory diseases (MRR, 2.3; 95% CI, 1.2-4.2) was significantly higher among nonparticipants than among participants. Standardized mortality ratio for the studied outcomes tended to be increased among nonparticipants and was generally decreased among participants.

Conclusion: Individuals who might benefit most from screening are overrepresented among nonparticipants. This self-selection may attenuate the cost-effectiveness of screening programs on a population level. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1163–8)
CYP1A1, GSTM1, and GSTT1 Polymorphisms, Smoking, and Lung Cancer Risk in a Pooled Analysis among Asian Populations
Authors: Lee Kyoung-Mu , Kang Daehee , Clapper Margie L. , Ingelman-Sundberg Magnus , Ono-Kihara Masko , Kiyohara Chikako , Min Shen , Lan Qing , Le Marchand Loic , Lin Pinpin , Lung Maria Li , Pinarbasi Hatice , Pisani Paola , Srivatanakul Petcharin , Seow Adeline , Sugimura Haruhiko , Tokudome Shinkan , Yokota Jun , Taioli Emanuela
Published: May 2008

To evaluate the roles of CYP1A1 polymorphisms [Ile462Val and T6235C (MspI)] and deletion of GSTM1 and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 6235C variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; Ptrend = 0.003). In haplotype analysis, 462Val-6235T and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with TT genotype (Pinteraction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction = 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1120–6)