Advances in cancer research:highlights from the 97th annual meeting of American Association for Cancer Research,2006
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《中华医药杂志》英文版
[Abstract] The American Association for Cancer Research (AACR) annual meeting is the most important cancer research meeting in the world. The 97th annual meeting was held on 1-5 April 2006 in Washington DC. Over 16 000 cancer research professionals were drawn to the meetingplace from thousands of miles around the globe. Programs included forums and special sessions, symposia and minisymposia, meet-the-expert sunrise sessions and new concepts in organ site research sessions, the public forum and poster sessions, educational sessions and methods workshops, as well as an exhibit show. Beginning with the opening plenary session titled “Looking into the future of cancer therapy”, sessions and symposia focusing on new and promising therapeutic approaches launched. All the programs were presented by world-renowned experts in a wide variety of disciplines, including cancer genetics, molecular diagnostics and therapeutics, chemistry, imaging, clinical research, stem cell biology and so on. No matter for junior investigators seeking new knowledge or for senior scientist requiring updates on the latest developments in the cancer field, the meeting could fulfill the needs for all the participants. This article tries to review the major breaking news and highlight researches in the AACR 97th annual meeting.
[Key words] neoplasms;molecular diagnostics techniques;stem cell;prevention biomedical research
INTRODUCTION The 97th annual meeting of the American Association for Cancer Research (AACR) was held in Washington DC on 1~5 April 2006. AACR is the oldest and largest scientific organization in the world focusing on every aspect of high-quality and innovative cancer research. It's annual meeting is the world's largest and most comprehensive gathering of professionals in the cancer field, which encompassed basic, translational and clinical research. The 97th annual meeting drew over 16 000 participants from the cancer research community. This year's theme was centered on new and promising therapeutic approaches.The program included 18 forums and special sessions, 46 symposia, over 50 minisymposia, nearly 60 meet-the-expert sunrise sessions, 14 new concepts in organ site research sessions, the public forum, 7 poster sessions featuring nearly 6,000 abstracts, 34 educational sessions and 6 methods workshops spanning nanotechnology, animal models of cancer, drug design/development and clinical trials design, as well as an exhibit show featuring over 800 exhibits from industry, government, publishing, non-profit and advocacy organizations. All the programs were delivered by top scientists in the cancer research fields. Some highlights of the 97th annual meeting are reviewed as follows.
CELLULAR AND MOLECULAR BIOLOGY
CpG methylation is an important component of epigenetic silencing during development. Hypermethylation of tumor suppressor and DNA repair genes can contribute to malignant transformation, which has been most extensively documented in colorectal carcinomas. Methylated promoters are repressed by CpG binding repressor proteins. Kaiso, a BTB/POZ zinc-finger protein, binds to heavily methylated promoters with high affinity and is a potent repressor. Lopes et al from Albert Einstein College of Medicine (USA)，hypothesized that kaiso played a critical role in colon cancer pathogenesis by silencing methylated tumor suppressor and DNA repair genes. They found that kaiso was bound to the methylated promoters of the p16 and HIC1 in colon cancer cells by chromatin immunoprecipitations and that silencing of these genes as well as other methylated
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
Correspondence to Dr William Chi-Shing Cho，Room 1305, 13/F, Block R, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong
Tel: 852-29585441 Fax:852-29585455 Email: williamcscho@gmail.com
tumor suppressor and DNA repair proteins were relieved by kaiso RNAi knockdown. Kaiso is concluded to be an important mediator of oncogenic epigenetic silencing colon epithelium and a potential therapeutic target in colon cancer[1].
Inactivation of regulatory genes by aberrant DNA methylation in the 5' region of their promoters is a hallmark of cancer. The reversible nature of DNA methylation makes it an ideal target for epigenetic therapy in which aberrant DNA methylation is reversed with the use of demethylating agents and reactivation of methylation-silenced genes is observed. Yoo et al from University of Southern California (USA) demonstrated that zebularine, a DNA methylation inhibitor, was preferentially active in cancer cells comparing to normal fibroblasts, due to higher activity of uridine/cytidine kinase which was responsible for phosphorylating zebularine into its monophosphate moiety and to increase the rate of incorporation of the drug into DNA in cancer cells[2].
Cyclin-dependent kinases (cdks) are universally overactive in tumor cells and represent potential anti-neoplastic drug targets. Recent data suggest the depletion of cdk2 activity alone does not lead to antiproliferative effects in cancer cells. Cai et al from Dana Farber Cancer Institute (USA) used siRNA technology to inducibly deplete cdk2, cdk1 and both together from NCI-H1299 non-small cell lung cancer and U2OS osteosarcoma cells. Depletion of cdk2 activity alone led to a subtle antiproliferative defect in NCI-1299 cells, with slowing of G1 progression following release from a nocodazole-induced mitotic block. Combined depletion of cdk2, cdk1 and cdk9 could induce apoptosis in tumor cells and these cdks represented a rational subset of the cdk family for drug targeting[3]. Besides, Macias et al of North Carolina State University (USA) demonstrated that cdk4 expression results in increased malignant progression in epithelial tissues. They suggested that embryonic expression of cdk4 resulted in a growth advantage and further selection of a cell population gave rise to aggressive carcinomas in synergism with a second alteration[4].
The estrogen receptor alpha (ER) gene is silenced in human breast cancer tumors. Loss of ER gene expression is associated with insensitivity to endocrine therapy. Previous studies show that the interplay between histone deacetylases and DNA methyltransferase (DNMTs) is a potential mechanism for inactivation of the ER gene. Zhou et al from Johns Hopkins University (USA) found that the physical association of DNMT1 with heat shock protein 90 (hsp90) was shown by coimmunoprecipitation experiments. LBH induced acetylation of hsp90, thereby inhibited the association of DNMT1 with hsp90, and promoted polyubiquitylation and degradation of DNMT1. Deletion of the N-terminal 120 amino acids blocked LBH-mediated ubiquitination of DNMT1, indicated that the N-terminal domain of DNMT1 was essential for its degradation. Their findings provide a novel mechanism by which histone deacetylase inhibitors can restore the silenced ER gene by accelerating the proteasomal degradation of DNMT1, and reorganizing the heterochromatin-associated proteins[5].
Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes (tsgs). One such histone modification, particularly at H3 and H4, is methylation at specific lysine residues. While histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 was reported before. Abbosh et al from University of Pittsburgh (USA) demonstrated that overexpression of mutant histone sequences H3K27 in mammalian cells represented a novel tool for studying epigenetic mechanisms. Their findings confirm the significance of H3-K27 methylation as a target for epigenetic-based cancer therapies[6].
Little is known about the regulation of microRNA (miRNA) expression, although the biological importance of these non-coding RNAs is becoming increasingly apparent. miRNAs are expressed in a tissue and tumor specific manner, implying that they may be subject to epigenetic control. Saito et al from Norris Comprehensive Cancer Center (USA) found that miR-127, which is embedded in CpG island, was highly induced from its own promoter after treatment. Further studies with cell lines revealed that miR-127 was expressed as a part of miRNA cluster in normal fibroblasts but silenced in cancer cells, and that induction after treatment was more pronounced in cancer cells compared to normal fibroblasts. In addition, a proto-oncogene BCL6, which was involved in the pathogenesis of B-cell lymphoma and was a potential target of miR-127, was translationally downregulated after treatment. These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors, and that induction of some miRNAs by epigenetic treatment may be a novel strategy for anticancer therapy[7].
Hypoxia inducible factor-1α (HIF1α) is a transcription factor that is a master regulator of oxygen homeostasis. A splice variant of HIF1α and HIF1α785 misses exon 11 from its oxygen dependent degradation domain. This region encodes the lysine that is critical for enhancing HIF1α degradation. ARD1 acetylates this critical lysine residue, in turn accelerates HIF1α degradation via the ubiquitin proteasome pathway by increasing its affinity for the Von Hippel Lindau tumor suppressor, an E3 ubiquitin ligase. Verifying by RT-PCR and Western blot, Mills et al from Edwards School of Medicine (USA) used a lentiviral based expression system to determine the effects of HIF1α and HIF1α785 overexpression in primary normal human melanocytes and in radial growth phase melanoma cells. Infected cells can be assayed for response to chemotherapeutic drugs, anchorage-independent growth and tumor formation in athymic mice[8].
Chemokine-chemokine receptor interactions play significant roles in prostate cancer cell survival, growth and metastasis. Singh et al from Morehouse School of Medicine (USA) demonstrated that CC chemokine receptor-9 (CCR9) was expressed by prostate cancer cells and CCR9-CCL25 interactions played a significant role in prostate cancer cell migration and invasion. Using tissue microarray analysis, they confirmed that the expression of CCR9 was higher in patients with advanced disease. Their data suggested that CCL25-induced motility, invasion and bone endothelial cell adhesion by prostate cancer cells, which was only partially pertussis toxin and wortamin sensitive. The expression of CCR9 by prostate carcinomas and CCL25 by bone marrow cells affected prostate cancer progression. The ability to detect CCL25 in patient serum may represent a new marker for monitoring prostate cancer progression[9].
Rapamycin is the inhibitor of mammalian target of rapamycin (mTOR). Ikezoe et al from UCLA School of Medicine (USA) found that when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Both LY294002 and rapamycin downregulated the levels of c-Myc and Cyclin D1 proteins in these cells, and their combination of both further decreased the levels of these cell cycle-regulating proteins. Longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with cancers in which this signaling is activated[10].
Epidermal growth factor (EGF) stimulation of mammary epithelial cells inhibits differentiation and apoptosis. EGF activates the phosphatidylinositol-3-kinase (PI-3-K) pathway in mammary epithelial cells, and breast tumors with constitutive PI-3-K activation exhibit resistance to chemotherapy. Galbaugh et al from Uniformed Services University of Health Sciences (USA) found that the inhibition of PI3K or mTOR abolished the activation of p70S6 kinase (p70S6K) by EGF in HC11 cells, suggested that PI-3-K signaling via p70S6K contributing to the EGF block of lactogenic differentiation. Additional investigation determined that EGF activated p70S6K, resulting in the phosphorylation of RPS6, eIF4e and 4EBP1 via PI-3-K dependent mechanisms. This data demonstrated that the EGF-induced activation of PI-3-K influenced translational control of proteins involving in the regulation of lactogenic differentiation. Since EGF stimulates the expression of SOCS1, blocking PI-3-K/mTOR signaling inhibits SOCS1 expression and prevents downregulation of Jak2/Stat5 by SOCS1, dissection of EGF induction of PI-3-K signaling reveals a novel role for translational control in the regulation of lactogenic differentiation[11].
Hepatocyte growth factor (HGF) and its receptor Met are present in most malignant mesothelioma tumors, suggesting that their expression is involved in mesothelioma progression. Previous studies suggested that Met signaling contributed to chemotaxis, growth, invasion and angiogenesis. Ramos-Nino et al from University of Vermont (USA) demonstrated that signaling by HGF strongly phosphorylated ERK5 in six mesothelioma cell lines. Decreased activation of ERK5 by inhibiting its activator, MEK5 with a siRNA construct, reduced the growth effect of HGF in these cells. They showed that ERK5 activation by HGF was dependent on the phosphatidylinositol 3-kinase pathway. These results suggest that the ERK5 pathway may be a therapeutic target in mesothelioma[12].
TUMOR BIOLOGY AND CARCINOGENESIS
Angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone of the renin-angiotensin system, is a molecular regulator of blood pressure and natriuresis. Soto-Pantoja et al from Wake Forest University (USA) found that as tumors were limited in size in the absence of neovascularization, administration of Ang-(1-7) might serve as a novel therapeutic agent for the treatment of any cancer expressing the selective Ang-(1-7) receptor[13].
There is currently no available therapy to overcome advanced androgen-independent and chemotherapy-resistant prostate cancer. The growth and survival of all neoplasms is dependent on a viable vasculature. Busby et al from Anderson Cancer Center (USA) implanted PC-3MM2-MDR prostate cancer cells into the prostates of nude mice, exhibiting a 76-fold increased resistance to taxanes. They found the inhibition of VEGF-R and EGF-R phosphorylation on tumor cells and tumor-associated endothelial cells by AEE788 and paclitaxel overcame chemotherapy-resistance prostate cancer by inducing apoptosis in tumor-associated endothelial cells, leading to apoptosis of MDR prostate cancer cells in the prostate and regional lymph nodes[14].
Utilizing qRT-PCR and siRNA lentiviruses, Liu et al from University of Michigan (USA) demonstrated a tumor stem cell model, in which Bmi-1 played an important role in the self-renewal of both normal and tumorigenic mammary stem cells with disregulation of Bmi-1 promoting carcinogenesis. Since tumor stem cells may drive tumor formation, targeting components of Bmi-1 regulated pathways represent a rationale strategy to eliminate this important cancer cell population[15].
Using fluorescence-activated cell sorting and immunohistochemical analysis, Reddy et al from MD Anderson Cancer Center (USA) found that human CD34+CD45+ and CD34-CD45+ cells migrated to Ewing's tumors and differentiated into cells expressing human vascular endothelial cadherin. There existed several distinct stem cell subpopulations which were capable of incorporating into the vascular network of a growing Ewing's tumor. Knowledge of the specific stem cell subpopulations involved will significantly further the understanding of the vasculogenesis process in Ewing's sarcoma[16].
The tumor suppressor protein, Pten, is commonly inactivated in human malignancies, including breast cancer. Lehal et al from University of Toronto (Canada) generated tumorspheres from Pten mutant tumors. These tumorspheres could be propagated in ultra-low attachment plates in DMEM/F12 media supplemented with EGF, FGF and B-27. They expressed both luminal and myo-epithelial cell markers when plated on collagen-coated slides. Understanding Pten-dependent tumor initiation may open new avenues for therapeutic interventions for breast cancer treatment[17].
CD44 is a multi-functional protein involved in cell adhesion and signaling. Patrawala et al from Anderson Cancer Center (USA) found that CD44+ prostate cancer cell population was enriched in tumorigenic and metastatic progenitor cells[18].
Blood vessels in solid tumors are structurally and functionally aberrant comparing to vessels in normal tissue. Charalambous et al from University of Southern California (USA) demonstrated that tumor-derived brain endothelial cells had properties of senescent cells. Their findings propose a novel aspect of tumor-endothelial cell interaction, whereby tumors not only stimulate angiogenesis, but also induce endothelial cells to become senescent[19].
Winter et al from Fred Hutchinson Cancer Research Center (USA) used the transgenic adenocarcinoma of the mouse prostate models to investigate the molecular mechanisms that contribute to initiation and progression of prostate cancer, with particular attention toward angiogenesis. They established a novel technique to quantitate vasculature in 3D following in vivo labeling with FITC-conjugated Lycopersicon esculentum (tomato plant) lectin. Using confocal microscopy, anti-angiopoietin-2 (Ang2) therapy inhibited tumor angiogenesis in mice, suggested that anti-FGFR1 therapy might inhibit angiogenesis in part by restoring normal expression of Ang1 and Ang2. This genetically engineered mouse model can be used as a pre-clinical model to evaluate the anti-angiogenic efficacy of the FGFR inhibitor PD173074[20].
The vascular endothelial growth factor (VEGF) is a major tumor angiogenic factor. One of its receptors, VEGF receptor-2 (VEGFR-2), is overexpressed in tumor and neovascular endothelial cells. Fiszman et al from University of Buenos Aires (Argentina) showed that their monoclonal antibodies anti VEGFR-2 might be useful as a tracer for in vivo tumor localization and eventually for the follow up of the disease[21].
Nitric oxide (NO) is a highly reactive free radical implicated in many physiological functions and diseases, such as ulcerative colitis. It can post-translationally modify cellular proteins, thereby alters their activity. NO can react with certain amino acids, particularly cysteines and tyrosines. In addition to protein modifications, it can damage DNA by deamination of adenine, guanine and cytosine to produce hypoxanthine, xanthine and uracil. NO also alters fatty acid metabolism to produce lipid peroxidation byproducts that react with DNA to produce 1,N66-ethenoadenine, 3,N4-ethenocysteine and N2,3-ethenoguanine. Each of these adducts is mutagenic. Jones et al from University of South Carolina (USA) suggested that NO could alter the activity of methylpurine DNA glycosylase by post-translational modification. Their findings raise the possibility that altered activity of methylpurine DNA glycosylase in base excision repair pathway by NO inducing post-translational modification contributes to mutagenesis[22].
Nonsteroidal antiinflammatory drug (NSAID) treatment exhibits antitumor properties on several tumor models, including mammary cancers. The canonical targets of NSAIDs are cyclooxygenases (COXs). Peluffo et al from Angel H Roffo Oncology Institute (Argentina) proposed that celecoxib and dimethylcelecoxib induced a reduction in the progression of these mammary adenocarcinomas in a COX-2-independent manner, modulating Akt, p38, NFκB and JNK signaling pathways[23].
CHEMISTRY
An et al from Georgetown University (USA) developed a MALDI-TOF/TOF methods for analysis of serum peptides enriched by denaturing ultrafiltration. Using newly developed PSO-SVM computational methods, the peptides were efficient at distinguishing stage Ⅰ and Ⅱ tumors and at distinguishing serum of HCC patients from serum of patients with cirrhosis. They discovered six peptides that identified HCC with high prediction accuracy. A combination of six markers significantly improved the prediction accuracy of individual markers. These peptides may be useful in examining progression of chronic hepatitis C viral infection to malignancy[24].
CLINICAL RESEARCH
Mutation-directed therapy shows clinical efficacy in several human cancers. Accurate detection of mutations in activated oncogenes is thus of increasing clinical importance. However, the sensitivity of DNA sequencing - the current standard for mutation diagnosis - is limited by stromal contamination and heterogeneity in tumor biopsies. Using a massively parallel microreactor-based sequencing-by-synthesis technology (picotiter plate sequencing) to generate over 200 000 sequencing reads per reaction from clonally amplified single DNA molecules, Thomas et al from Dana Farber Cancer Institute (UA) found that picotiter plate sequencing revealed clinically meaningful mutations that were undetectable by Sanger sequencing. Thus parallel single-template sequencing may enable enhanced sensitivity for molecular diagnosis of stromally admixed cancer specimens and thereby facilitate selection of targeted cancer therapies[25].
Based on the preclinical activity of gemcitabine (Gem) and imatinib mesylate (IM) in combination, a phase I study of Gem+IM is developed to determine the maximum tolerated doses for Gem and IM when administered in combination. Ali et al from Cancer Institute of New Jersey (USA) found that the addition of IM to Gem increased the activity and range of Gem. Responses and protracted stable disease were noted. Limiting IM duration decreased the Gem toxicity and permitted its dose escalation[26].
ENDOCRINOLOGY
Estrogens play an important role in the development and progression of breast cancer. Aromatase inhibitors block the synthesis of estrogen, superior to antiestrogens, they may replace tamoxifen as first line treatment for postmenopausal estrogen receptor positive breast cancer patients. Sabnis et al from University of Maryland (USA) hypothesized that inhibition of both Her-2 mediated tyrosine kinase signaling and mTOR dependent translation could provide better inhibition of proliferation of breast cancer cells that were refractory to aromatase inhibitor and might also restore responsiveness to aromatase inhibitor[27].
EPIDEMIOLOGY
Chronic infection with hepatitis B or C virus and alcoholic cirrhosis are well known major risk factors for liver cancer. Hwang et al from Seoul National University (Republic of Korea) demonstrated that high level of serum glucose might raise the risk of liver cancer in Korea. The association was independent of hepatitis infection and drinking history. Their study suggests that insulin resistance and glucose intolerance can be associated with carcinogenesis mechanism of liver cancer[28].
EXPERIMENTAL AND MOLECULAR
THERAPEUTICS
Lung cancer is the deadliest cancer with a 15% survival rate.NPRL2 is one of the candidate tsgs residing on a 120 kb homozygous deletion region in human chromosome 3P21.3. Ueda et al from University of Texas (USA) suggested that NPRL2 could function as an important effector in facilitating DNA-damage-induced apoptosis by activation of multiple pro-apoptotic effectors and regulation of key components in DNA-damage-induced apoptosis and cell cycle checkpoint pathways and that treatment with NPRL2 nanoparticle plus CDDP might effectively overcome CDDP resistance in lung cancer cells[29].
Weekes et al from Johns Hopkins University (USA) developed a pancreas xenograft model utilizing live explanted human adenocarcinoma obtained during pancreaticoduodenectomy as platform for the development of novel therapeutic agents. Treated with mTOR inhibitor and CCI-779, activation of CXCR4 by its ligand, SDF-1, resulted in phosphorylation of Akt and mTOR activation. mTOR blockage by CCI-779 is suggested to be effective against pancreatic tumors and SDF-1 may mediate resistance to mTOR inhibition via upregulation of HIF-1α in this model[30].
5-Fluorouracil (5FU) is the most widely used anticancer agent for treatment of gastrointestinal cancers. Since many tumors show primary or acquired resistance, it is clinically meaningful to better understand the molecular basis underlying the mechanism of resistance to 5FU. UMP-CMP kinase (UMPK) plays an important role in the activation of 5FU to 5F-UTP, which serves as a substrate for RNA synthesis. Humeniuk et al from UMDNJ-Graduate School of Biomedical Sciences (USA) examined methylation status of the CpG island in both sensitive and 5-FU resistant cells. Their results showed that a majority of the CpG sites within this region were methylated in both cell lines but the pattern of methylation was different in 5FU sensitive and resistant cells. Treatment of 5-FU resistant cells with 5-Aza-deoxycytidine, an inhibitor of DNA hyper-methylation, resulted in elevated expression of UMPK and restored sensitivity to 5FU treatment. This data supported the important role of DNA methylation in suppressing UMPK expression. Their findings provide new insights into mechanisms of resistance to 5FU in colorectal cancer and mechanisms of UMPK gene regulation[31].
Rodriguez et al from CA and California Institute of Technology (USA) provided a better understanding of the binding properties of novel molecules and paved the way for the rational design of future studies aimed to the treatment of hematopoietic malignancies. They found that antihuman transferrin receptor (TfR) IgG3-(Av) and its parental antibody (antihuman TfR IgG3) preferentially bind transferrin receptor TfR1 over TfR2 as demonstrated by protein and cell ELISA. The antibodies were able to bind, in a dose dependent manner, a soluble form of the TfR1 (sTfR1) that existed in human blood as a result of proteolysis of the membrane-bound receptor. The lack of binding of these molecules to TfR2 and their binding to the soluble form of TfR1 is expected to have an impact in their pharmacokinetic properties[32].
Using siRNA in HEK293 cells to examine the conservation of mechanisms, Waardenburg et al from St Jude Children's Research Hospital (USA) demonstrated that imboqiotom conjugation 9 functions protect human cells from camptothecin[33].
McKallip et al from University of South Carolina (USA) examined the effect of non-psychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. They demonstrated that cannabidiol was a potent inducer of apoptosis in leukemia and that this mechanism might be related to the regulation of NAPDH oxidases and the production of reactive oxygen species[34].
PREVENTION RESEARCH
Pancreatic ductal adenocarcinoma is a uniquely lethal disease for which there is no cure. Cruz-Monserrate of Sealy Center for Cancer Cell Biology (USA) suggested that integrin α6β4 was important for the invasive phenotype of pancreatic carcinomas, increased expression and redistribution of integrin α6β4 from the hemidesmosomes was involved in the invasiveness of many cancers. He found that integrin α6β4 was a useful marker to distinguish pancreatitis from pancreatic cancer due to the characteristic staining pattern. Overexpression of integrin α6β4 noted in early pancreatic intraepithelial lesions suggests that this represents an early event in the progression of pancreatic cancers[35].
Prostate cancer is the second leading cause of cancer death among men. Resveratrol, a phytoalexin, is found in red grapes and red wine. In vitro studies show that resveratrol can inhibit the initiation, promotion and progression stages of carcinogenesis. Cook et al from University of Alabama (USA) showed that resveratrol suppressed the insulin-like growth factor 1 signaling pathway, possibly contributing to its chemopreventive actions in the prostate. On the other hand, there is a notion that vitamin E can prevent prostate cancer where a low dose of α-tocopherol reduced prostate cancer risk in smokers[36]. Bosland et al from New York University (USA) found that α-tocopherol did not protect against prostate cancer but promoted mammary cancer in male NBL rats treated with testosterone and estradiol-17-β[37].
Multiple lines of compelling evidence from epidemiological and laboratory studies support an inverse association between consumption of garlic and the risk of cancer. Chemopreventive effects of garlic are attributed to its oil-soluble sulfur ingredients, such as diallyl sulfide, diallyl disulfide and diallyl trisulfide, but their underlying molecular mechanisms remain largely unresolved. Na et al from Seoul National University (Republic of Korea) found that diallyl trisulfide-induced apoptosis in human breast carcinoma-7 cells was mediated through accumulation of reactive oxygen species with subsequent activation of c-jun N-terminal kinase that catalyzed phosphorylation of Bcl-2 at Ser 70[38].
Green tea polyphenols (GTP) are effective chemopreventive agents in inhibition of a variety of carcinogen-induced tumorigenesis in the in vitro bioassays and in vivo animal models for different target organ sites, including aflatoxin-induced liver tumors. Yu et al from Texas Tech University (USA) demonstrated relative long-term safety of GTP in human intervention and administration with GTP might have protective effect against human hepatocellular carcinogenesis[39].
In the 97th annual meeting, new technologies and the resulting explosion in biological information provide a wealth of tools for physician, clinician-scientist and healthcare professionals regarding diagnosis, treatment and prevention of cancer. Delegates can share the latest discoveries and trends across the entire spectrum of cancer research. For those who did not attend the meeting, this review may serve as a highlight of this international cancer research meeting.
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33.Van Waardenburg RC, Duda D, Lancaster CS, et al. Distinct functional domains of the SUMO Ubc9 conjugating enzyme regulate cell resistance to genotoxic stress [abstract]. Am Assoc Cancer Res，2006，47: 578.
34.McKallip RJ, Jia W, Schlomer J, et al. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22 phox and Nox4 expression [abstract]. Am Assoc Cancer Res，2006，47: 1084.
35.Cruz-Monserrate Z, Qiu S, Evers BM, et al. Altered expression of integrin α6β4 as a marker to distinguish pancreatic cancer from chronic pancreatitis [abstract]. Am Assoc Cancer Res，2006，47: 337.
36.Cook LM, Harper C, Lamartiniere C. Resveratrol in the diet regulates IGF-1 signaling proteins in the prostate of rats [abstract]. Am Assoc Cancer Res，2006，47: 534.
37.Bosland MC, Horton LH, Lasano S. Alpha-tocopherol does not protect against prostate cancer but promotes mammary cancer in male NBL rats treated with testosterone and estradiol-17-beta [abstract]. Am Assoc Cancer Res，2006，47: 925-926.
38.Na HK, Kim EH, Kim DH, et al. Diallyl trisulfide induces apoptosis in human breast cancer cells through generation of ROS and activation of c-Jun N-terminal kinase [abstract]. Am Assoc Cancer Res，2006，47: 1317-1318.
39.Yu J, Huang T, Zhang L, et al. Chemoprevention trial of green tea polyphenols in high-risk population of liver cancer in southern Guangxi, China [abstract]. Am Assoc Cancer Res，2006，47: 1148.
(Editor Guo Hui-ling)(William Chi-Shing Cho)
[Key words] neoplasms;molecular diagnostics techniques;stem cell;prevention biomedical research
INTRODUCTION The 97th annual meeting of the American Association for Cancer Research (AACR) was held in Washington DC on 1~5 April 2006. AACR is the oldest and largest scientific organization in the world focusing on every aspect of high-quality and innovative cancer research. It's annual meeting is the world's largest and most comprehensive gathering of professionals in the cancer field, which encompassed basic, translational and clinical research. The 97th annual meeting drew over 16 000 participants from the cancer research community. This year's theme was centered on new and promising therapeutic approaches.The program included 18 forums and special sessions, 46 symposia, over 50 minisymposia, nearly 60 meet-the-expert sunrise sessions, 14 new concepts in organ site research sessions, the public forum, 7 poster sessions featuring nearly 6,000 abstracts, 34 educational sessions and 6 methods workshops spanning nanotechnology, animal models of cancer, drug design/development and clinical trials design, as well as an exhibit show featuring over 800 exhibits from industry, government, publishing, non-profit and advocacy organizations. All the programs were delivered by top scientists in the cancer research fields. Some highlights of the 97th annual meeting are reviewed as follows.
CELLULAR AND MOLECULAR BIOLOGY
CpG methylation is an important component of epigenetic silencing during development. Hypermethylation of tumor suppressor and DNA repair genes can contribute to malignant transformation, which has been most extensively documented in colorectal carcinomas. Methylated promoters are repressed by CpG binding repressor proteins. Kaiso, a BTB/POZ zinc-finger protein, binds to heavily methylated promoters with high affinity and is a potent repressor. Lopes et al from Albert Einstein College of Medicine (USA)，hypothesized that kaiso played a critical role in colon cancer pathogenesis by silencing methylated tumor suppressor and DNA repair genes. They found that kaiso was bound to the methylated promoters of the p16 and HIC1 in colon cancer cells by chromatin immunoprecipitations and that silencing of these genes as well as other methylated
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
Correspondence to Dr William Chi-Shing Cho，Room 1305, 13/F, Block R, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong
Tel: 852-29585441 Fax:852-29585455 Email: williamcscho@gmail.com
tumor suppressor and DNA repair proteins were relieved by kaiso RNAi knockdown. Kaiso is concluded to be an important mediator of oncogenic epigenetic silencing colon epithelium and a potential therapeutic target in colon cancer[1].
Inactivation of regulatory genes by aberrant DNA methylation in the 5' region of their promoters is a hallmark of cancer. The reversible nature of DNA methylation makes it an ideal target for epigenetic therapy in which aberrant DNA methylation is reversed with the use of demethylating agents and reactivation of methylation-silenced genes is observed. Yoo et al from University of Southern California (USA) demonstrated that zebularine, a DNA methylation inhibitor, was preferentially active in cancer cells comparing to normal fibroblasts, due to higher activity of uridine/cytidine kinase which was responsible for phosphorylating zebularine into its monophosphate moiety and to increase the rate of incorporation of the drug into DNA in cancer cells[2].
Cyclin-dependent kinases (cdks) are universally overactive in tumor cells and represent potential anti-neoplastic drug targets. Recent data suggest the depletion of cdk2 activity alone does not lead to antiproliferative effects in cancer cells. Cai et al from Dana Farber Cancer Institute (USA) used siRNA technology to inducibly deplete cdk2, cdk1 and both together from NCI-H1299 non-small cell lung cancer and U2OS osteosarcoma cells. Depletion of cdk2 activity alone led to a subtle antiproliferative defect in NCI-1299 cells, with slowing of G1 progression following release from a nocodazole-induced mitotic block. Combined depletion of cdk2, cdk1 and cdk9 could induce apoptosis in tumor cells and these cdks represented a rational subset of the cdk family for drug targeting[3]. Besides, Macias et al of North Carolina State University (USA) demonstrated that cdk4 expression results in increased malignant progression in epithelial tissues. They suggested that embryonic expression of cdk4 resulted in a growth advantage and further selection of a cell population gave rise to aggressive carcinomas in synergism with a second alteration[4].
The estrogen receptor alpha (ER) gene is silenced in human breast cancer tumors. Loss of ER gene expression is associated with insensitivity to endocrine therapy. Previous studies show that the interplay between histone deacetylases and DNA methyltransferase (DNMTs) is a potential mechanism for inactivation of the ER gene. Zhou et al from Johns Hopkins University (USA) found that the physical association of DNMT1 with heat shock protein 90 (hsp90) was shown by coimmunoprecipitation experiments. LBH induced acetylation of hsp90, thereby inhibited the association of DNMT1 with hsp90, and promoted polyubiquitylation and degradation of DNMT1. Deletion of the N-terminal 120 amino acids blocked LBH-mediated ubiquitination of DNMT1, indicated that the N-terminal domain of DNMT1 was essential for its degradation. Their findings provide a novel mechanism by which histone deacetylase inhibitors can restore the silenced ER gene by accelerating the proteasomal degradation of DNMT1, and reorganizing the heterochromatin-associated proteins[5].
Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes (tsgs). One such histone modification, particularly at H3 and H4, is methylation at specific lysine residues. While histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 was reported before. Abbosh et al from University of Pittsburgh (USA) demonstrated that overexpression of mutant histone sequences H3K27 in mammalian cells represented a novel tool for studying epigenetic mechanisms. Their findings confirm the significance of H3-K27 methylation as a target for epigenetic-based cancer therapies[6].
Little is known about the regulation of microRNA (miRNA) expression, although the biological importance of these non-coding RNAs is becoming increasingly apparent. miRNAs are expressed in a tissue and tumor specific manner, implying that they may be subject to epigenetic control. Saito et al from Norris Comprehensive Cancer Center (USA) found that miR-127, which is embedded in CpG island, was highly induced from its own promoter after treatment. Further studies with cell lines revealed that miR-127 was expressed as a part of miRNA cluster in normal fibroblasts but silenced in cancer cells, and that induction after treatment was more pronounced in cancer cells compared to normal fibroblasts. In addition, a proto-oncogene BCL6, which was involved in the pathogenesis of B-cell lymphoma and was a potential target of miR-127, was translationally downregulated after treatment. These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors, and that induction of some miRNAs by epigenetic treatment may be a novel strategy for anticancer therapy[7].
Hypoxia inducible factor-1α (HIF1α) is a transcription factor that is a master regulator of oxygen homeostasis. A splice variant of HIF1α and HIF1α785 misses exon 11 from its oxygen dependent degradation domain. This region encodes the lysine that is critical for enhancing HIF1α degradation. ARD1 acetylates this critical lysine residue, in turn accelerates HIF1α degradation via the ubiquitin proteasome pathway by increasing its affinity for the Von Hippel Lindau tumor suppressor, an E3 ubiquitin ligase. Verifying by RT-PCR and Western blot, Mills et al from Edwards School of Medicine (USA) used a lentiviral based expression system to determine the effects of HIF1α and HIF1α785 overexpression in primary normal human melanocytes and in radial growth phase melanoma cells. Infected cells can be assayed for response to chemotherapeutic drugs, anchorage-independent growth and tumor formation in athymic mice[8].
Chemokine-chemokine receptor interactions play significant roles in prostate cancer cell survival, growth and metastasis. Singh et al from Morehouse School of Medicine (USA) demonstrated that CC chemokine receptor-9 (CCR9) was expressed by prostate cancer cells and CCR9-CCL25 interactions played a significant role in prostate cancer cell migration and invasion. Using tissue microarray analysis, they confirmed that the expression of CCR9 was higher in patients with advanced disease. Their data suggested that CCL25-induced motility, invasion and bone endothelial cell adhesion by prostate cancer cells, which was only partially pertussis toxin and wortamin sensitive. The expression of CCR9 by prostate carcinomas and CCL25 by bone marrow cells affected prostate cancer progression. The ability to detect CCL25 in patient serum may represent a new marker for monitoring prostate cancer progression[9].
Rapamycin is the inhibitor of mammalian target of rapamycin (mTOR). Ikezoe et al from UCLA School of Medicine (USA) found that when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Both LY294002 and rapamycin downregulated the levels of c-Myc and Cyclin D1 proteins in these cells, and their combination of both further decreased the levels of these cell cycle-regulating proteins. Longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with cancers in which this signaling is activated[10].
Epidermal growth factor (EGF) stimulation of mammary epithelial cells inhibits differentiation and apoptosis. EGF activates the phosphatidylinositol-3-kinase (PI-3-K) pathway in mammary epithelial cells, and breast tumors with constitutive PI-3-K activation exhibit resistance to chemotherapy. Galbaugh et al from Uniformed Services University of Health Sciences (USA) found that the inhibition of PI3K or mTOR abolished the activation of p70S6 kinase (p70S6K) by EGF in HC11 cells, suggested that PI-3-K signaling via p70S6K contributing to the EGF block of lactogenic differentiation. Additional investigation determined that EGF activated p70S6K, resulting in the phosphorylation of RPS6, eIF4e and 4EBP1 via PI-3-K dependent mechanisms. This data demonstrated that the EGF-induced activation of PI-3-K influenced translational control of proteins involving in the regulation of lactogenic differentiation. Since EGF stimulates the expression of SOCS1, blocking PI-3-K/mTOR signaling inhibits SOCS1 expression and prevents downregulation of Jak2/Stat5 by SOCS1, dissection of EGF induction of PI-3-K signaling reveals a novel role for translational control in the regulation of lactogenic differentiation[11].
Hepatocyte growth factor (HGF) and its receptor Met are present in most malignant mesothelioma tumors, suggesting that their expression is involved in mesothelioma progression. Previous studies suggested that Met signaling contributed to chemotaxis, growth, invasion and angiogenesis. Ramos-Nino et al from University of Vermont (USA) demonstrated that signaling by HGF strongly phosphorylated ERK5 in six mesothelioma cell lines. Decreased activation of ERK5 by inhibiting its activator, MEK5 with a siRNA construct, reduced the growth effect of HGF in these cells. They showed that ERK5 activation by HGF was dependent on the phosphatidylinositol 3-kinase pathway. These results suggest that the ERK5 pathway may be a therapeutic target in mesothelioma[12].
TUMOR BIOLOGY AND CARCINOGENESIS
Angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone of the renin-angiotensin system, is a molecular regulator of blood pressure and natriuresis. Soto-Pantoja et al from Wake Forest University (USA) found that as tumors were limited in size in the absence of neovascularization, administration of Ang-(1-7) might serve as a novel therapeutic agent for the treatment of any cancer expressing the selective Ang-(1-7) receptor[13].
There is currently no available therapy to overcome advanced androgen-independent and chemotherapy-resistant prostate cancer. The growth and survival of all neoplasms is dependent on a viable vasculature. Busby et al from Anderson Cancer Center (USA) implanted PC-3MM2-MDR prostate cancer cells into the prostates of nude mice, exhibiting a 76-fold increased resistance to taxanes. They found the inhibition of VEGF-R and EGF-R phosphorylation on tumor cells and tumor-associated endothelial cells by AEE788 and paclitaxel overcame chemotherapy-resistance prostate cancer by inducing apoptosis in tumor-associated endothelial cells, leading to apoptosis of MDR prostate cancer cells in the prostate and regional lymph nodes[14].
Utilizing qRT-PCR and siRNA lentiviruses, Liu et al from University of Michigan (USA) demonstrated a tumor stem cell model, in which Bmi-1 played an important role in the self-renewal of both normal and tumorigenic mammary stem cells with disregulation of Bmi-1 promoting carcinogenesis. Since tumor stem cells may drive tumor formation, targeting components of Bmi-1 regulated pathways represent a rationale strategy to eliminate this important cancer cell population[15].
Using fluorescence-activated cell sorting and immunohistochemical analysis, Reddy et al from MD Anderson Cancer Center (USA) found that human CD34+CD45+ and CD34-CD45+ cells migrated to Ewing's tumors and differentiated into cells expressing human vascular endothelial cadherin. There existed several distinct stem cell subpopulations which were capable of incorporating into the vascular network of a growing Ewing's tumor. Knowledge of the specific stem cell subpopulations involved will significantly further the understanding of the vasculogenesis process in Ewing's sarcoma[16].
The tumor suppressor protein, Pten, is commonly inactivated in human malignancies, including breast cancer. Lehal et al from University of Toronto (Canada) generated tumorspheres from Pten mutant tumors. These tumorspheres could be propagated in ultra-low attachment plates in DMEM/F12 media supplemented with EGF, FGF and B-27. They expressed both luminal and myo-epithelial cell markers when plated on collagen-coated slides. Understanding Pten-dependent tumor initiation may open new avenues for therapeutic interventions for breast cancer treatment[17].
CD44 is a multi-functional protein involved in cell adhesion and signaling. Patrawala et al from Anderson Cancer Center (USA) found that CD44+ prostate cancer cell population was enriched in tumorigenic and metastatic progenitor cells[18].
Blood vessels in solid tumors are structurally and functionally aberrant comparing to vessels in normal tissue. Charalambous et al from University of Southern California (USA) demonstrated that tumor-derived brain endothelial cells had properties of senescent cells. Their findings propose a novel aspect of tumor-endothelial cell interaction, whereby tumors not only stimulate angiogenesis, but also induce endothelial cells to become senescent[19].
Winter et al from Fred Hutchinson Cancer Research Center (USA) used the transgenic adenocarcinoma of the mouse prostate models to investigate the molecular mechanisms that contribute to initiation and progression of prostate cancer, with particular attention toward angiogenesis. They established a novel technique to quantitate vasculature in 3D following in vivo labeling with FITC-conjugated Lycopersicon esculentum (tomato plant) lectin. Using confocal microscopy, anti-angiopoietin-2 (Ang2) therapy inhibited tumor angiogenesis in mice, suggested that anti-FGFR1 therapy might inhibit angiogenesis in part by restoring normal expression of Ang1 and Ang2. This genetically engineered mouse model can be used as a pre-clinical model to evaluate the anti-angiogenic efficacy of the FGFR inhibitor PD173074[20].
The vascular endothelial growth factor (VEGF) is a major tumor angiogenic factor. One of its receptors, VEGF receptor-2 (VEGFR-2), is overexpressed in tumor and neovascular endothelial cells. Fiszman et al from University of Buenos Aires (Argentina) showed that their monoclonal antibodies anti VEGFR-2 might be useful as a tracer for in vivo tumor localization and eventually for the follow up of the disease[21].
Nitric oxide (NO) is a highly reactive free radical implicated in many physiological functions and diseases, such as ulcerative colitis. It can post-translationally modify cellular proteins, thereby alters their activity. NO can react with certain amino acids, particularly cysteines and tyrosines. In addition to protein modifications, it can damage DNA by deamination of adenine, guanine and cytosine to produce hypoxanthine, xanthine and uracil. NO also alters fatty acid metabolism to produce lipid peroxidation byproducts that react with DNA to produce 1,N66-ethenoadenine, 3,N4-ethenocysteine and N2,3-ethenoguanine. Each of these adducts is mutagenic. Jones et al from University of South Carolina (USA) suggested that NO could alter the activity of methylpurine DNA glycosylase by post-translational modification. Their findings raise the possibility that altered activity of methylpurine DNA glycosylase in base excision repair pathway by NO inducing post-translational modification contributes to mutagenesis[22].
Nonsteroidal antiinflammatory drug (NSAID) treatment exhibits antitumor properties on several tumor models, including mammary cancers. The canonical targets of NSAIDs are cyclooxygenases (COXs). Peluffo et al from Angel H Roffo Oncology Institute (Argentina) proposed that celecoxib and dimethylcelecoxib induced a reduction in the progression of these mammary adenocarcinomas in a COX-2-independent manner, modulating Akt, p38, NFκB and JNK signaling pathways[23].
CHEMISTRY
An et al from Georgetown University (USA) developed a MALDI-TOF/TOF methods for analysis of serum peptides enriched by denaturing ultrafiltration. Using newly developed PSO-SVM computational methods, the peptides were efficient at distinguishing stage Ⅰ and Ⅱ tumors and at distinguishing serum of HCC patients from serum of patients with cirrhosis. They discovered six peptides that identified HCC with high prediction accuracy. A combination of six markers significantly improved the prediction accuracy of individual markers. These peptides may be useful in examining progression of chronic hepatitis C viral infection to malignancy[24].
CLINICAL RESEARCH
Mutation-directed therapy shows clinical efficacy in several human cancers. Accurate detection of mutations in activated oncogenes is thus of increasing clinical importance. However, the sensitivity of DNA sequencing - the current standard for mutation diagnosis - is limited by stromal contamination and heterogeneity in tumor biopsies. Using a massively parallel microreactor-based sequencing-by-synthesis technology (picotiter plate sequencing) to generate over 200 000 sequencing reads per reaction from clonally amplified single DNA molecules, Thomas et al from Dana Farber Cancer Institute (UA) found that picotiter plate sequencing revealed clinically meaningful mutations that were undetectable by Sanger sequencing. Thus parallel single-template sequencing may enable enhanced sensitivity for molecular diagnosis of stromally admixed cancer specimens and thereby facilitate selection of targeted cancer therapies[25].
Based on the preclinical activity of gemcitabine (Gem) and imatinib mesylate (IM) in combination, a phase I study of Gem+IM is developed to determine the maximum tolerated doses for Gem and IM when administered in combination. Ali et al from Cancer Institute of New Jersey (USA) found that the addition of IM to Gem increased the activity and range of Gem. Responses and protracted stable disease were noted. Limiting IM duration decreased the Gem toxicity and permitted its dose escalation[26].
ENDOCRINOLOGY
Estrogens play an important role in the development and progression of breast cancer. Aromatase inhibitors block the synthesis of estrogen, superior to antiestrogens, they may replace tamoxifen as first line treatment for postmenopausal estrogen receptor positive breast cancer patients. Sabnis et al from University of Maryland (USA) hypothesized that inhibition of both Her-2 mediated tyrosine kinase signaling and mTOR dependent translation could provide better inhibition of proliferation of breast cancer cells that were refractory to aromatase inhibitor and might also restore responsiveness to aromatase inhibitor[27].
EPIDEMIOLOGY
Chronic infection with hepatitis B or C virus and alcoholic cirrhosis are well known major risk factors for liver cancer. Hwang et al from Seoul National University (Republic of Korea) demonstrated that high level of serum glucose might raise the risk of liver cancer in Korea. The association was independent of hepatitis infection and drinking history. Their study suggests that insulin resistance and glucose intolerance can be associated with carcinogenesis mechanism of liver cancer[28].
EXPERIMENTAL AND MOLECULAR
THERAPEUTICS
Lung cancer is the deadliest cancer with a 15% survival rate.NPRL2 is one of the candidate tsgs residing on a 120 kb homozygous deletion region in human chromosome 3P21.3. Ueda et al from University of Texas (USA) suggested that NPRL2 could function as an important effector in facilitating DNA-damage-induced apoptosis by activation of multiple pro-apoptotic effectors and regulation of key components in DNA-damage-induced apoptosis and cell cycle checkpoint pathways and that treatment with NPRL2 nanoparticle plus CDDP might effectively overcome CDDP resistance in lung cancer cells[29].
Weekes et al from Johns Hopkins University (USA) developed a pancreas xenograft model utilizing live explanted human adenocarcinoma obtained during pancreaticoduodenectomy as platform for the development of novel therapeutic agents. Treated with mTOR inhibitor and CCI-779, activation of CXCR4 by its ligand, SDF-1, resulted in phosphorylation of Akt and mTOR activation. mTOR blockage by CCI-779 is suggested to be effective against pancreatic tumors and SDF-1 may mediate resistance to mTOR inhibition via upregulation of HIF-1α in this model[30].
5-Fluorouracil (5FU) is the most widely used anticancer agent for treatment of gastrointestinal cancers. Since many tumors show primary or acquired resistance, it is clinically meaningful to better understand the molecular basis underlying the mechanism of resistance to 5FU. UMP-CMP kinase (UMPK) plays an important role in the activation of 5FU to 5F-UTP, which serves as a substrate for RNA synthesis. Humeniuk et al from UMDNJ-Graduate School of Biomedical Sciences (USA) examined methylation status of the CpG island in both sensitive and 5-FU resistant cells. Their results showed that a majority of the CpG sites within this region were methylated in both cell lines but the pattern of methylation was different in 5FU sensitive and resistant cells. Treatment of 5-FU resistant cells with 5-Aza-deoxycytidine, an inhibitor of DNA hyper-methylation, resulted in elevated expression of UMPK and restored sensitivity to 5FU treatment. This data supported the important role of DNA methylation in suppressing UMPK expression. Their findings provide new insights into mechanisms of resistance to 5FU in colorectal cancer and mechanisms of UMPK gene regulation[31].
Rodriguez et al from CA and California Institute of Technology (USA) provided a better understanding of the binding properties of novel molecules and paved the way for the rational design of future studies aimed to the treatment of hematopoietic malignancies. They found that antihuman transferrin receptor (TfR) IgG3-(Av) and its parental antibody (antihuman TfR IgG3) preferentially bind transferrin receptor TfR1 over TfR2 as demonstrated by protein and cell ELISA. The antibodies were able to bind, in a dose dependent manner, a soluble form of the TfR1 (sTfR1) that existed in human blood as a result of proteolysis of the membrane-bound receptor. The lack of binding of these molecules to TfR2 and their binding to the soluble form of TfR1 is expected to have an impact in their pharmacokinetic properties[32].
Using siRNA in HEK293 cells to examine the conservation of mechanisms, Waardenburg et al from St Jude Children's Research Hospital (USA) demonstrated that imboqiotom conjugation 9 functions protect human cells from camptothecin[33].
McKallip et al from University of South Carolina (USA) examined the effect of non-psychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. They demonstrated that cannabidiol was a potent inducer of apoptosis in leukemia and that this mechanism might be related to the regulation of NAPDH oxidases and the production of reactive oxygen species[34].
PREVENTION RESEARCH
Pancreatic ductal adenocarcinoma is a uniquely lethal disease for which there is no cure. Cruz-Monserrate of Sealy Center for Cancer Cell Biology (USA) suggested that integrin α6β4 was important for the invasive phenotype of pancreatic carcinomas, increased expression and redistribution of integrin α6β4 from the hemidesmosomes was involved in the invasiveness of many cancers. He found that integrin α6β4 was a useful marker to distinguish pancreatitis from pancreatic cancer due to the characteristic staining pattern. Overexpression of integrin α6β4 noted in early pancreatic intraepithelial lesions suggests that this represents an early event in the progression of pancreatic cancers[35].
Prostate cancer is the second leading cause of cancer death among men. Resveratrol, a phytoalexin, is found in red grapes and red wine. In vitro studies show that resveratrol can inhibit the initiation, promotion and progression stages of carcinogenesis. Cook et al from University of Alabama (USA) showed that resveratrol suppressed the insulin-like growth factor 1 signaling pathway, possibly contributing to its chemopreventive actions in the prostate. On the other hand, there is a notion that vitamin E can prevent prostate cancer where a low dose of α-tocopherol reduced prostate cancer risk in smokers[36]. Bosland et al from New York University (USA) found that α-tocopherol did not protect against prostate cancer but promoted mammary cancer in male NBL rats treated with testosterone and estradiol-17-β[37].
Multiple lines of compelling evidence from epidemiological and laboratory studies support an inverse association between consumption of garlic and the risk of cancer. Chemopreventive effects of garlic are attributed to its oil-soluble sulfur ingredients, such as diallyl sulfide, diallyl disulfide and diallyl trisulfide, but their underlying molecular mechanisms remain largely unresolved. Na et al from Seoul National University (Republic of Korea) found that diallyl trisulfide-induced apoptosis in human breast carcinoma-7 cells was mediated through accumulation of reactive oxygen species with subsequent activation of c-jun N-terminal kinase that catalyzed phosphorylation of Bcl-2 at Ser 70[38].
Green tea polyphenols (GTP) are effective chemopreventive agents in inhibition of a variety of carcinogen-induced tumorigenesis in the in vitro bioassays and in vivo animal models for different target organ sites, including aflatoxin-induced liver tumors. Yu et al from Texas Tech University (USA) demonstrated relative long-term safety of GTP in human intervention and administration with GTP might have protective effect against human hepatocellular carcinogenesis[39].
In the 97th annual meeting, new technologies and the resulting explosion in biological information provide a wealth of tools for physician, clinician-scientist and healthcare professionals regarding diagnosis, treatment and prevention of cancer. Delegates can share the latest discoveries and trends across the entire spectrum of cancer research. For those who did not attend the meeting, this review may serve as a highlight of this international cancer research meeting.
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(Editor Guo Hui-ling)(William Chi-Shing Cho)