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Arbyn, Marc; Ronco, Guglielmo; Cuzick, Jack; Wentzensen, Nicolas; Castle, Philip E.
doi: 10.1002/ijc.24774pmid: 19626591
Excellent recommendations exist for studying therapeutic and diagnostic questions. We observe that good guidelines on assessment of evidence for screening questions are currently lacking. Guidelines for diagnostic research (STARD), involving systematic application of the reference test (gold standard) to all subjects of large study populations, are not pertinent in situations of screening for disease that is currently not yet present. A five‐step framework is proposed for assessing the potential use of a biomarker as a screening tool for cervical cancer: i) correlation studies establishing a trend between the rate of biomarker expression and severity of neoplasia; ii) diagnostic studies in a clinical setting where all women are submitted to verification by the reference standard; iii) biobank‐based studies with assessment in archived cytology samples of the biomarker in cervical cancer cases and controls; iv) prospective cohort studies with baseline assessment of the biomarker and monitoring of disease; v) randomised intervention trials aiming to observe reduced incidence of cancer (or its surrogate, severe dysplasia) in the experimental arm at subsequent screening rounds. The 5‐phases framework should guide researchers and test developers in planning assessment of new biomarkers and protect clinicians and stakeholders against premature claims for insufficiently evaluated products. © 2009 UICC.
Miura, Motohiro; Ohnishi, Naomi; Tanaka, Shinya; Yanagiya, Kohei; Hatakeyama, Masanori
doi: 10.1002/ijc.24740pmid: 19588494
Infection with cagA‐positive Helicobacter pylori is associated with gastric carcinoma. The cagA‐encoded CagA protein is delivered into gastric epithelial cells and, upon tyrosine phosphorylation at the C‐terminal EPIYA segments, binds and deregulates SHP‐2 oncoprotein. On the basis of the differential alignment of the EPIYA segments, CagA can be subdivided into Western CagA, which is produced by H. pylori isolated in Western countries, and East Asian CagA, which is produced by H. pylori circulating in East Asian countries. Western CagA contains EPIYA‐A, EPIYA‐B and variable numbers of EPIYA‐C segments, whereas East Asian CagA contains EPIYA‐A, EPIYA‐B and variable numbers of EPIYA‐D segments. Upon tyrosine phosphorylation, EPIYA‐C and EPIYA‐D, respectively, serve as low‐affinity and high‐affinity SHP‐2‐binding sites. We previously reported that systemic expression of East Asian CagA (CagA‐ABDD) induces gastrointestinal and hematopoietic malignancies in mice. In this study, we generated transgenic mice that systemically express Western CagA (CagA‐ABCCC), the levels of which are comparable to those in mice expressing East Asian CagA. The mice developed gastric epithelial hypertrophy and gastrointestinal tumors and also showed lymphoid abnormality but not myeloid abnormalities such as granulocytosis and myeloid leukemia found in mice carrying East Asian CagA. The incidence of tumors in mice expressing Western CagA was significantly lower than that in mice expressing East Asian CagA. Our results indicate that Western CagA is qualitatively less oncogenic than East Asian CagA. Differential oncogenic potential of geographically distinct CagA isoforms may contribute to the differential prevalence of gastric carcinoma between East Asian countries and Western countries. © 2009 UICC
Mutoh, Michihiro; Komiya, Masami; Teraoka, Naoya; Ueno, Toshiya; Takahashi, Mami; Kitahashi, Tsukasa; Sugimura, Takashi; Wakabayashi, Keiji
doi: 10.1002/ijc.24667pmid: 19544529
Apc‐deficient Min mice feature low expression of lipoprotein lipase (LPL), high concentration of serum triglyceride (TG), fatty change of the liver and large numbers of intestinal polyps. We have reported that induction of LPL expression reduces serum lipid, especially TG, improves fatty change of the liver and inhibits intestinal polyp formation in the mice. In this study, fatty change/lipid accumulation in intestinal mucosa and polyps in Min mice were analyzed by Oil‐red O staining and electron microscopy. A number of large lipid droplets were found in the epithelia of the upper part of polyps. On the other hand, small lipid droplets were only slightly observed at the tip of the villi in non‐tumoros parts of the small intestine of Min mice and in the villi of wild‐type mice. Moreover, low‐density lipoprotein receptor (LDLR) was overexpressed in the area where lipid droplets were observed. The expression levels of LDLR mRNA in the intestinal polyps of Min mice were ∼3 times higher compared to those in the non‐tumoros parts. Remarkable expression of cyclooxygenase‐2 was mainly distributed in stromal cells and some in epithelial cells. It is speculated that lipid accumulation in the intestinal polyps may play an important role in intestinal polyp formation in Apc‐deficient mice. © 2009 UICC
Liu, Funan; Li, Xiaodong; Wang, Chunyu; Cai, Xinze; Du, Zhongmin; Xu, Huimian; Li, Feng
doi: 10.1002/ijc.24588pmid: 19610058
p21‐activated kinase 1 (Pak1), a serine/threonine kinase, has been implicated in cytoskeletal remodelling, cell motility, apoptosis and transformation. However, the role of Pak1 in gastric cancer remains unclear. In this study, we detected Pak1 expression in gastric cancer tissues from 40 patients by western blot. Overexpression of Pak1 was associated with progression, metastasis and prognosis of gastric cancer. In addition, we found that knockdown of Pak1 expression significantly inhibited anchorage‐dependent and anchorage‐independent growth in gastric cancer cells, and markedly inhibited gastric cancer cell xenograft tumor growth. In further study, data showed that Pak1 could regulate the expression of cyclin B1 at the mRNA and protein levels, and impact the subcellular distribution and the promoter activity of cyclin B1. Results from deletion and mutant analysis supplied a new NF‐κB binding sites at position ‐321 of cyclin B1 promoter, and indicated that Pak1 regulated the transcription of cyclin B1 in gastric cancer through NF‐κB. In conclusion, Pak1 may be a potential prognostic marker and therapeutic target in gastric cancer. © 2009 UICC
Torosyan, Yelizaveta; Simakova, Olga; Naga, Shanmugam; Mezhevaya, Katerina; Leighton, Ximena; Diaz, Juan; Huang, Wei; Pollard, Harvey; Srivastava, Meera
doi: 10.1002/ijc.24592pmid: 19610065
The tumor suppressor role of annexin‐A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/−)‐mice and by ANXA7 loss in human cancers, especially in hormone‐resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild‐type (WT)‐ANXA7 and dominant‐negative (DN)‐ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT‐ANXA7 demonstrated profound cytotoxicityin androgen‐sensitive LNCaP as well as in the androgen‐resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen‐sensitive LNCaP, WT‐ANXA7 decreased low‐molecular‐weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho‐RB1 ratio. In contrast, DN‐ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW‐AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN‐ANXA7 cytotoxicity. According to the microarray‐based Ingenuity Pathways Analysis, a major WT‐ANXA7 effect in androgen‐sensitive LNCaP constituted of upregulation of the RB1‐binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F‐mediated transcription. However, DN‐ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation‐promoting ERK5, thereby maintaining the RB‐dependent repression of E2F‐mediated apoptosis in LNcaP. On the other hand, in androgen‐resistant cells, WT‐ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB‐associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC.
Yu, Le; Wu, William Ka Kei; Li, Zhi Jie; Li, Hai Tao; Wu, Ya Chun; Cho, Chi Hin
doi: 10.1002/ijc.24607pmid: 19623651
Overexpression of cyclooxygenase‐2 (COX‐2) and elevation of its derivative prostaglandin E2 (PGE2) are implicated in human esophageal squamous cell carcinoma. The expression of c‐Myc, an oncogenic transcription factor, is also upregulated in this malignant disease. This study sought to elucidate whether a functional connection exists between COX‐2/PGE2 and c‐Myc in esophageal squamous cell carcinoma. Results showed that PGE2 substantially increased the proliferation of cultured esophageal squamous cell carcinoma cells. In this regard, PGE2 substantially increased the mRNA and protein expression of c‐Myc and its association with the binding partner Max. Knockdown of c‐Myc by RNA interference also significantly attenuated PGE2‐induced cell proliferation. Further, mechanistic study revealed that PGE2 increased the protein stability and nuclear accumulation of c‐Myc via phosphorylation on serine 62 in an extracellular signal regulated kinase (ERK)‐dependent manner. To this end, ERK activation by PGE2 was completely abolished by protein kinase C (PKC) inhibitors. Moreover, the effect of PGE2 on c‐Myc expression was mimicked by EP2 receptor agonist. In addition, knockdown of EP2 receptor by EP2 siRNA attenuated PGE2‐induced c‐Myc expression. Collectively, our findings suggest that PGE2 upregulates c‐Myc via the EP2/PKC/ERK pathway. This study sheds new light on the carcinogenic mechanism of PGE2 in esophageal squamous cell carcinoma. © 2009 UICC
Vitali, Roberta; Mancini, Camillo; Cesi, Vincenzo; Tanno, Barbara; Piscitelli, Marta; Mancuso, Mariateresa; Sesti, Fabiola; Pasquali, Emanuela; Calabretta, Bruno; Dominici, Carlo; Raschellà, Giuseppe
doi: 10.1002/ijc.24606
Haughian, James M.; Reno, Elaine M.; Thorne, Alicia M.; Bradford, Andrew P.
doi: 10.1002/ijc.24633pmid: 19672862
Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCα, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCα protein grew slower, formed fewer colonies in anchorage‐independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCα knockdown increased levels of the cyclin‐dependent kinase (CDK) inhibitors p21Cip1/WAF1 (p21) and p27Kip1 (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCα knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase‐3β (GSK‐3β). PKCα knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCα regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCα expression, with foci of elevated PKCα staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCα signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK‐dependent proliferative pathways. Thus, targeting PKCα may provide novel therapeutic options in endometrial tumors. © 2009 UICC
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RhoB, a tumor suppressor, has emerged as an interesting cancer target, and extensive studies aimed at understanding its role in apoptosis have been performed. In our study, we investigated the involvement of RhoB‐interacting molecules in apoptosis. To identify RhoB‐interacting proteins, we performed yeast‐two hybrid screening assays using RhoB as a bait and isolated TNFAIP1, a TNFα‐induced protein containing the BTB/POZ domain. The interaction between RhoB and TNFAIP1 was demonstrated in vivo through coimmunoprecipitation studies and in vitro binding assays. RFP‐TNFAIP1 was found to be partially colocalized with EGFP‐RhoB. The partial colocalization of RhoB and TNFAIP1 in endosomes suggests that RhoB‐TNFAIP1 interactions may have a functional role in apoptosis. TNFAIP1 elicited proapoptotic activity, while simultaneous expression of RhoB and TNFAIP1 resulted in a dramatic increase in apoptosis in HeLa cells. Furthermore, knockdown of RhoB using siRNA clearly rescued cells from apoptosis induced by TNFAIP1. This finding suggests that interactions between RhoB and TNFAIP1 are crucial for induction of apoptosis in HeLa cells. The observation of increased SAPK/JNK phosphorylation in apoptotic cells and the finding that a JNK inhibitor suppressed apoptosis indicates that SAPK/JNK signaling may be involved in apoptosis induced by RhoB‐TNFAIP1 interactions. In conclusion, we found that RhoB interacts with TNFAIP1 to regulate apoptosis via a SAPK/JNK‐mediated signal transduction mechanism. © 2009 UICC
Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second‐generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC50 in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage‐independent growth and, in some instances, induced senescence and apoptosis. In HTLA‐230 cells, Dasatinib treatment caused down‐regulation of c‐Kit and c‐Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA‐230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA‐230 cells, tumour growth was significantly inhibited at the dose of 30 mg/(kg day) when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC50= 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60 mg/(kg day) but only when treatment was started 1 day after injection. However, the anti‐tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour. © 2009 UICC