Showing papers in "International Journal of Cancer in 2006"

The global health burden of infection-associated cancers in the year 2002.

Abstract: Several infectious agents are considered to be causes of cancer in humans. The fraction of the different types of cancer, and of all cancers worldwide and in different regions, has been estimated using several methods; primarily by reviewing the evidence for the strength of the association (relative risk) and the prevalence of infection in different world areas. The estimated total of infection-attributable cancer in the year 2002 is 1.9 million cases, or 17.8% of the global cancer burden. The principal agents are the bacterium Helicobacter pylori (5.5% of all cancer), the human papilloma viruses (5.2%), the hepatitis B and C viruses (4.9%), Epstein-Barr virus (1%), human immunodeficiency virus (HIV) together with the human herpes virus 8 (0.9%). Relatively less important causes of cancer are the schistosomes (0.1%), human T-cell lymphotropic virus type I (0.03%) and the liver flukes (0.02%). There would be 26.3% fewer cancers in developing countries (1.5 million cases per year) and 7.7% in developed countries (390,000 cases) if these infectious diseases were prevented. The attributable fraction at the specific sites varies from 100% of cervix cancers attributable to the papilloma viruses to a tiny proportion (0.4%) of liver cancers (worldwide) caused by liver flukes.

Overview of the European and North American studies on HPV testing in primary cervical cancer screening.

Abstract: Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35–49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy. © 2006 Wiley-Liss, Inc.

Expression profiling identifies microRNA signature in pancreatic cancer

Abstract: microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real-time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR-155, miR-21, miR-221 and miR-222) as well as those not previously reported in cancer (miR-376a and miR-301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real-time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR-221, -376a and -301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma.

Gallbladder cancer worldwide: geographical distribution and risk factors.

Abstract: Gallbladder cancer is a relatively rare neoplasm that shows, however, high incidence rates in certain world populations. The interplay of genetic susceptibility, lifestyle factors and infections in gallbladder carcinogenesis is still poorly understood. Age-adjusted rates were calculated by cancer registry-based data. Epidemiological studies on gallbladder cancer were selected through searches of literature, and relative risks were abstracted for major risk factors. The highest gallbladder cancer incidence rates worldwide were reported for women in Delhi, India (21.5/100,000), South Karachi, Pakistan (13.8/100,000) and Quito, Ecuador (12.9/100,000). High incidence was found in Korea and Japan and some central and eastern European countries. Female-to-male incidence ratios were generally around 3, but ranged from 1 in Far East Asia to over 5 in Spain and Colombia. History of gallstones was the strongest risk factor for gallbladder cancer, with a pooled relative risk (RR) of 4.9 [95% confidence interval (CI): 3.3-7.4]. Consistent associations were also present with obesity, multiparity and chronic infections like Salmonella typhi and S. paratyphi [pooled RR 4.8 (95% CI: 1.4-17.3)] and Helicobacter bilis and H. pylori [pooled RR 4.3 (95% CI: 2.1-8.8)]. Differences in incidence ratios point to variations in gallbladder cancer aetiology in different populations. Diagnosis of gallstones and removal of gallbladder currently represent the keystone to gallbladder cancer prevention, but interventions able to prevent obesity, cholecystitis and gallstone formation should be assessed.

Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies.

Abstract: Accumulating epidemiologic evidence indicates that high consumption of red meat and of processed meat may increase the risk of colorectal cancer. We quantitatively assessed the association between red meat and processed meat consumption and the risk of colorectal cancer in a meta-analysis of prospective studies published through March 2006. Random-effects models were used to pool study results and to assess dose-response relationships. We identified 15 prospective studies on red meat (involving 7,367 cases) and 14 prospective studies on processed meat consumption (7,903 cases). The summary relative risks (RRs) of colorectal cancer for the highest vs. the lowest intake categories were 1.28 (95% confidence interval (CI) = 1.15-1.42) for red meat and 1.20 (95% CI = 1.11-1.31) for processed meat. The estimated summary RRs were 1.28 (95% CI = 1.18-1.39) for an increase of 120 g/day of red meat and 1.09 (95% CI = 1.05-1.13) for an increase of 30 g/day of processed meat. Consumption of red meat and processed meat was positively associated with risk of both colon and rectal cancer, although the association with red meat appeared to be stronger for rectal cancer. In 3 studies that reported results for subsites in the colon, high consumption of processed meat was associated with an increased risk of distal colon cancer but not of proximal colon cancer. The results of this meta-analysis of prospective studies support the hypothesis that high consumption of red meat and of processed meat is associated with an increased risk of colorectal cancer.

Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers

Abstract: Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers have generated enormous interest, because they predict for sensitivity to TK inhibitors (TKIs). While mutational status is of great importance in determining response to TKIs, it is not the sole factor, and evidence is accumulating that EGFR gene amplification, other members of the EGFR family (HER2, HER3) and genes downstream of EGFR signaling (KRAS, BRAF), may be involved in cancer pathogenesis and the response of TKIs. EGFR mutations occur in highly selected subpopulations of lung cancer patients: adenocarcinoma histology, never-smoker status, East Asian ethnicity and female gender. The recent finding of "a resistance associated" mutation for TKIs also provides new insights into this complicated mechanism. Thus, molecular-based studies to analyze the biological functions and to assess TKI sensitivity depending on the type of mutations are required. Epidemiological studies to identify possible carcinogenic factor(s) affecting different subpopulations are also of interest. In addition, for optimal therapeutic approach a comprehensive understanding of the genes related to EGFR signaling pathway, including RAS/RAF/MAPK and PI3K-AKT pathways, are required.

Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases.

Abstract: Soft tissue sarcomas (STS) are a heterogeneous group of uncommon tumors that show a broad range of differentiation that may reflect etiologic distinction. Routine tabulations of STS are not morphology-specific. Further, the lack of inclusion of sarcomas arising in all organs in most standard evaluations underestimates the true rates. We analyzed the 1978–2001 Surveillance, Epidemiology and End Results program incidence rates of STS regardless of primary site, except bones and joints, using the 2002 criteria of the WHO classification. There were 26,758 cases available for analysis. Leiomyosarcomas accounted for 23.9%, malignant fibrous histiocytomas 17.1%, liposarcomas 11.5%, dermatofibrosarcomas 10.5%, rhabdomyosarcomas 4.6% and angiosarcomas 4.1%. Almost half (47.9%) of the sarcomas arose in the soft tissues, 14.0% in the skin and 7.0% in the uterus. Overall, incidence rates were highest among black women (6.26/100,000 woman-years) and the lowest among white women (4.60/100,000). Age-adjusted rates increased at 1.2% and 0.8% per year among white males and females, respectively, both trends statistically significant, while rates among blacks declined slightly. About 40% of leiomyosarcomas among women were uterine in origin, with a black/white rate ratio of 1.7. This rate ratio increased to 2.0 when we accounted for the lower prevalence of intact uteri among black compared to white women. Total STS rates rose exponentially with age. Rates for both uterine leiomyosarcoma and dermatofibrosarcoma increased rapidly during the childbearing years, peaking at about age 40 and 50, respectively. Incidence patterns of STS varied markedly by histologic type, supporting the notion that these tumors may be etiologically distinct. © 2006 Wiley-Liss, Inc.

Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer

Abstract: Smoking and alcohol are well-known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV-positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during 1970-2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Abstract: Folate receptor alpha (FRalpha) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRalpha levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRalpha might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRalpha gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRalpha in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRalpha levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRalpha-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions.

Chemokines and cancer.

Abstract: The chemokines are a superfamily of 41 human ligands and at least 18 receptors (Zlotnik and Yoshie 2000). They have been divided into inflammatory and homeostatic chemokines depending on their expression patterns. The inflammatory chemokines are generally those that are produced by cells of the immune system upon activation. The homeostatic chemokines are those whose expression is constitutive and are generally produced by nonimmune cells. The chemokines by and large have been considered to be important in the regulation of leukocyte traffic in the body. This has been shown most dramatically in the case of a few chemokine receptors, including CCR7 and CXCR5. CCR7 has two ligands, CCL19 and CCL21, whose expression is eliminated in a natural mutant mouse called the paucity of lymph node T cells (PLT) mouse. This is a mouse that arose naturally and was identified in an animal facility in Japan (Gunn 1998). As its name indicates, this mouse does not have many T cells in its lymph nodes. Careful analysis of the gene expression in this mouse showed that both CCL19 and CCL21 are not expressed in the lymph nodes of these mice (Gunn 1998).

Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies.

Abstract: Tobacco smoking has been classified as a cause of cervical cancer, but the effect of different patterns of smoking on risk is unclear. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 13,541 women with and 23,017 women without cervical carcinoma, from 23 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of carcinoma of the cervix in relation to tobacco smoking were calculated with stratification by study, age, sexual partners, age at first intercourse, oral contraceptive use and parity. Current smokers had a significantly increased risk of squamous cell carcinoma of the cervix compared to never smokers (RR = 1.60 (95% CI: 1.48-1.73), p<0.001). There was increased risk for past smokers also, though to a lesser extent (RR = 1.12 (1.01-1.25)), and there was no clear trend with time since stopping smoking (p-trend = 0.6). There was no association between smoking and adenocarcinoma of the cervix (RR = 0.89 (0.74-1.06) and 0.89 (0.72-1.10) for current and past smokers respectively), and the differences between the RRs for smoking and squamous cell and adenocarcinoma were statistically significant (current smoking p<0.001 and past smoking p = 0.01). In current smokers, the RR of squamous cell carcinoma increased with increasing number of cigarettes smoked per day and also with younger age at starting smoking (p<0.001 for each trend), but not with duration of smoking (p-trend = 0.3). Eight of the studies had tested women for cervical HPV-DNA, and in analyses restricted to women who tested positive, there was a significantly increased risk in current compared to never smokers for squamous cell carcinoma (RR = 1.95 (1.43-2.65)), but not for adenocarcinoma (RR = 1.06 (0.14-7.96)). In summary, smokers are at an increased risk of squamous cell but not of adenocarcinoma of the cervix. The risk of squamous cell carcinoma increases in current smokers with the number of cigarettes smoked per day and with younger age at starting smoking.

Variations in the age‐specific curves of human papillomavirus prevalence in women worldwide

Abstract: An inverse relationship between age and human papillomavirus (HPV) prevalence has been reported in many developed countries, but information on this relationship is scarce in many other parts of the world We carried out a cross-sectional study of sexually active women from the general population of 15 areas in 4 continents Similar standardised protocols for women's enrolment, cervical specimen collection and PCR-based assays for HPV testing were used HPV prevalence in different age groups was compared by study area 18,498 women aged 15-74 years were included Age-standardised HPV prevalence varied more than 10-fold between populations, as did the shape of age-specific curves HPV prevalence peaked below age 25 or 35, and declined with age in Italy, the Netherlands, Spain, Argentina, Korea and in Lampang, Thailand and Ho Chi Minh, Vietnam This was not the case in Songkla, Thailand nor Hanoi, Vietnam, where HPV prevalence was low in all age groups In Chile, Colombia and Mexico, a second peak of HPV prevalence was detected among older women In the poorest study areas in Asia (Shanxi, China and Dindigul, India), and in Nigeria, HPV prevalence was high across all age groups The substantial differences observed in age-specific curves of HPV prevalence between populations may have a variety of explanations These differences, however, underline that great caution should be used in inferring the natural history of HPV from age-specific prevalences

Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).

Abstract: It is considered that fruit and vegetable (FV 95% CI 0.35-1.22 per 100 g increase) and onion and garlic intake (calibrated HR 0.70; 95% CI 0.38-1.29 per 10 g increase). No evidence of association between fresh fruit intake and GC risk was observed. We found a negative but non significant association between citrus fruit intake and the cardia site (calibrated HR 0.77; 95% CI 0.47-1.22 per 100 g increase) while no association was observed with the non-cardia site. Regarding ACO, we found a non significant negative association for vegetable intake and for citrus intake (calibrated HRs 0.72; 95% CI 0.32-1.64 and 0.77; 95% CI 0.46-1.28 per 100 and 50 g increase, respectively). It seems that Hp infection does not modify the effect of F&V intake. Our study supports a possible protective role of vegetable intake in the intestinal type of GC and the ACO. Citrus fruit consumption may have a role in the protection against cardia GC and ACO.

Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro.

Abstract: Human tumors frequently escape immune destruction, despite the presence of cytotoxic T cells (CTL) recognizing tumor-associated antigens (TAA) We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumor-specific T cells We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominantly in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion

Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.

Abstract: Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration-dependent intracellular increase in O(o)(2)(-) and H(2)O(2) levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H(2)O(2) scavenger, induced a 4-fold increase in paclitaxel IC(50). Delaying NAC co-incubation by 4 hr, resulted in a 3-fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H(2)O(2) accumulation, but did not modify O(o)(2)(-) levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O(o)(2)(-) production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H(2)O(2.) To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H(2)O(2) is an early and crucial step for paclitaxel-induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity.

The burden of cancer attributable to alcohol drinking

Abstract: We estimated the number of cancer cases and deaths attributable to alcohol drinking in 2002 by sex and WHO subregion, based on relative risks of cancers of the oral cavity, pharynx, esophagus, liver, colon, rectum, larynx and female breast obtained from recent meta- and pooled analyses and data on prevalence of drinkers obtained from the WHO Global Burden of Disease project. A total of 389,100 cases of cancer are attributable to alcohol drinking worldwide, representing 3.6% of all cancers (5.2% in men, 1.7% in women). The corresponding figure for mortality is 232,900 deaths (3.5% of all cancer deaths). This proportion is particularly high among men in Central and Eastern Europe. Among women, breast cancer comprises 60% of alcohol-attributable cancers. Although our estimates are based on simplified assumptions, the burden of alcohol-associated cancer appears to be substantial and needs to be considered when making public health recommendations on alcohol drinking.

The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers

Abstract: The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the beta-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant beta2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established beta-blockers for the inhibition of metastases.

Fucosylated haptoglobin is a novel marker for pancreatic cancer : A detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation

Abstract: Changes in oligosaccharide structures have been reported in certain types of malignant transformations and, thus, could be used for tumor markers in certain types of cancer. In the case of pancreatic cancer cell lines, a variety of fucosylated proteins are secreted into their conditioned media. To identify fucosylated proteins in the serum of patients with pancreatic cancer, we performed western blot analyses using Aleuria Aurantica Lectin (AAL), which is specific for fucosylated structures. An approximately 40 kD protein was found to be highly fucosylated in pancreatic cancer and an N-terminal analysis revealed that it was the beta chain of haptoglobin. While the appearance of fucosylated haptoglobin has been reported in other diseases such as hepatocellular carcinoma, liver cirrhosis, gastric cancer and colon cancer, the incidence was significantly higher in the case of pancreatic cancer. Fucosylated haptoglobin was observed more frequently at the advanced stage of pancreatic cancer and disappeared after an operation. A mass spectrometry analysis of haptoglobin purified from the serum of patients with pancreatic cancer and the medium from a pancreatic cancer cell line, PSN-1, showed that the alpha 1-3/alpha 1-4/alpha 1-6 fucosylation of haptoglobin was increased in pancreatic cancer. When a hepatoma cell line, Hep3B, was cultured with the conditioned media from pancreatic cancer cells, haptoglobin secretion was dramatically increased. These findings suggest that fucosylated haptoglobin could serve as a novel marker for pancreatic cancer. Two possibilities were considered in terms of the fucosylation of haptoglobin. One is that pancreatic cancer cells, themselves, produce fucosylated haptoglobin; the other is that pancreatic cancer produces a factor, which induces the production of fucosylated haptoglobin in the liver.

Trends in testicular cancer incidence and mortality in 22 European countries: continuing increases in incidence and declines in mortality

Abstract: This study profiles testicular cancer incidence and mortality across Europe, and the effects of age, period and generational influences, using age-period-cohort modeling. Despite a 5-fold variation in incidence rates, there were consistent mean increases in incidence in each of the 12 European countries studied, ranging from around 6% per annum (Spain and Slovenia) to 1-2% (Norway). In contrast, declines in testicular cancer mortality of 3-6% per annum were observed in the 1980s and 1990s for the majority of the 22 countries studied, particularly in Northern and Western Europe. The mortality trends in several European countries were rather stable (Romania and Bulgaria) or increasing (Portugal and Croatia). Short-term attenuations in increasing cohort-specific risk of incidence were indicated among men born between 1940 and 1945 in 7 European countries. In Switzerland, successive generations born from the mid 1960s may have experienced a steadily declining risk of disease occurrence. While the underlying risk factors responsible remain elusive, the temporal and geographical variability in incidence may point to an epidemic in different phases in different countries-the result of country-specific differences in the prevalence of one or several ubiquitous and highly prevalent environmental determinants of the disease. Advances in treatment have led to major declines in mortality in many European countries from the mid 1970s, which has translated to cohorts of men at successively lower risk of death from the disease. Slower progress in the delivery of optimal care is however evident from the mortality trends in several lower-resource countries in Southern and Eastern Europe. The first beneficiaries of therapy in these populations may be those men born--rather than diagnosed--in the era of major breakthrough in testicular cancer care.

EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus.

Abstract: Overexpression of epidermal growth factor receptor (EGFR) is observed in many cancers, sometimes accompanied by gene amplification. Recently, several clinical therapies targeting EGFR were developed, but the eligibility criteria for these therapies is not fully established. To develop such eligibility criteria for esophageal squamous cell carcinoma (ESCC), we sought to clarify: (i) the exact frequency of EGFR overexpression, (ii) the relationship between protein overexpression and gene amplification, (iii) the relationship between gene amplification and specific gene mutations and (iv) the correlation between the status of EGFR and clinical or pathological features. Immunohistochemistry revealed that EGFR protein is overexpressed in 53 (50%) of the 106 ESCC examined. Fluorescence in situ hybridization (FISH) indicated clear EGFR gene amplification in 15 of the 53 tumors, somewhat higher EGFR copy in 32 cases, and no increase in 6 cases. Gene amplification was significantly associated with high level overexpression. Direct sequencing of exons 19 and 21 of EGFR revealed no mutations in 15 tumors exhibiting gene amplification, and no mutations in 25 tumors not exhibiting gene amplification. Overexpression of EGFR was significantly correlated with depth of invasion of the tumor. In conclusion, anti-EGFR therapies may be appropriate for patients with ESCC. We assume that combined analyses by immunohistochemistry/FISH would clarify aberrations in protein and gene function, and could help to identify those patients who may benefit from anti-EGFR therapy.

Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation.

Abstract: We have previously demonstrated that, following acquisition of endocrine resistance, breast cancer cells display an altered growth rate together with increased aggressive behaviour in vitro. Since dysfunctional cell–cell adhesive interactions can promote an aggressive phenotype, we investigated the integrity of this protein complex in our breast cancer model of tamoxifen resistance. In culture, tamoxifen-resistant MCF7 (TamR) cells grew as loosely packed colonies with loss of cell–cell junctions and demonstrated altered morphology characteristic of cells undergoing epithelialto-mesenchymal transition (EMT). Neutralising E-cadherin function promoted the invasion and inhibited the aggregation of endocrine-sensitive MCF7 cells, whilst having little effect on the behaviour of TamR cells. Additionally, TamR cells had increased levels of tyrosine-phosphorylated b-catenin, whilst serine/threoninephosphorylated b-catenin was decreased. These cells also displayed loss of association between b-catenin and E-cadherin, increased cytoplasmic and nuclear b-catenin and elevated transcription of b-catenin target genes known to be involved in tumour progression and EMT. Inhibition of EGFR kinase activity in TamR cells reduced b-catenin tyrosine phosphorylation, increased b-catenin–E-cadherin association and promoted cell–cell adhesion. In such treated cells, the association of b-catenin with Lef-1 and the transcription of c-myc, cyclin-D1, CD44 and COX-2 were also reduced. These results suggest that homotypic adhesion in tamoxifen-resistant breast cancer cells is dysfunctional due to EGFR-driven modulation of the phosphorylation status of b-catenin and may contribute to an enhanced aggressive phenotype and transition towards a mesenchymal phenotype in vitro.

MicroRNA and cancer: Current status and prospective

Abstract: Gene expression in normal cells is highly regulated by complex gene regulatory networks. Disruption of these networks may lead to cancer. Recent studies have revealed the existence of an abundant class of small nonprotein-coding regulatory RNAs, known as microRNAs (miRNAs). MiRNAs may regulate diverse biological processes including development, cell proliferation, differentiation and apoptosis, through suppressing the expression of their target genes. Posttranscriptional silencing of target genes by miRNAs occurs either by cleavage of homologous target messenger RNAs (mRNAs), or by inhibition of target protein synthesis. Computational predictions indicate that 1 miRNA may target on hundreds of genes, and suggest that over 50% of human protein-coding genes might be regulated by miRNAs. MiRNAs are receiving increased attention in cancer genomic research. We are beginning to understand that miRNAs may act as oncogenes and/or tumor suppressor genes within the molecular architecture of gene regulatory networks, thereby contributing to the development of cancer. MiRNAs may provide useful diagnostic and prognostic markers for cancer diagnosis and treatment, as well as serving as potential therapeutic targets or tools.

Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells

Abstract: Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2–5 μM) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (˜2.5 μM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 μM). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells. © 2006 Wiley-Liss, Inc.

Spectrum of cancers among HIV-infected persons in Africa: The Uganda AIDS-Cancer Registry Match Study

Abstract: Although more than 25 million people in sub-Saharan Africa have human immunodeficiency virus (HIV) infection, little is known regarding their cancer risk. We investigated cancer risk among persons with HIV/AIDS in Uganda using record-linkage. We linked records of 12,607 HIV-infected persons attending The AIDS Support Organization (TASO) in Kyadondo County from October 1988 through December 2002 to the Kampala Cancer Registry. We calculated standardized incidence ratios (SIRs) to identify increased cancer risks in the early (4-27 months after TASO registration), late (28-60 months), or combined (4-60 months) incidence periods. We identified 378 cancers (181 prevalent, 197 incident) among TASO participants. Of incident cancers, 137 (70%) were AIDS-defining cancers. Risk was increased in the early-incident period, compared to the general population, for the AIDS-defining cancers: Kaposi sarcoma (SIR 6.4, 95%CI 4.8-8.4), non-Hodgkin lymphoma (6.7, 1.8-17), and cervical carcinoma (2.4, 1.1-4.4). These three cancers were also increased in the combined periods. Risks of five non-AIDS-defining cancers were increased in the combined periods: Hodgkin lymphoma (5.7, 1.2-17) and cancers of the conjunctiva (SIR 4.0; 1.5-8.7), kidney (16, 1.8-58), thyroid (5.7, 1.1-16), and uterus (5.5, 1.5-14). Cancers of the breast, nasopharynx, and lung were increased either in the early or late incident periods only. Among 407 children, seven cancers were observed, of which five were Kaposi sarcoma. The application of a record-linkage design in Africa broadens the repertoire of epidemiological tools for studying HIV-infected populations. We confirm the increased risks of AIDS-defining cancers and report increased risks of a few non-AIDS-defining cancers.

Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update

Abstract: Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is approximately 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30-0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24-2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65).

Fibronectin as target for tumor therapy.

Abstract: During cancer progression, the extracellular matrix (ECM) of the tissue in which the tumor grows is extensively remodeled, both by degradation of preexisting ECM molecules and by the neosynthesis of ECM components, which in many cases are not present in the ECM of normal tissues. Fibronectin (FN), a class of high-molecular-weight adhesive glycoproteins, plays a prominent role in mediating ECM function, because of its high abundance and its interaction with cellular components. Furthermore, the generation of tumor-associated FN isoforms allows the development of specific ligands (e.g., antibodies), which can be used for the selective delivery of therapeutic agents to the tumor environment. In view of these considerations, it is not surprising that FN is being used as a target for biomolecular intervention, both for the development of inhibitory molecules that block the interaction of FN with integrins and other receptors on the cell surface, and for the development of ligand-based targeted imaging and therapeutic strategies. In this review, we briefly present the essential properties of FN, and we then focus on the therapeutic strategies that are currently in preclinical or clinical development and feature FN as a target, or that are based on FN fragments so as to promote tumor-growth inhibition.

Genome variation of human papillomavirus types: Phylogenetic and medical implications

Abstract: Human papillomaviruses (HPVs) are described as "types" based on their genome sequences and identified by a number. For example, HPV-6 is associated with genital warts, and HPV-16 with anogenital cancers. The genomes of many HPV types have been reisolated, sequenced and compared to reference "prototypes" countless times by laboratories throughout the world. It was found that each HPV type occurs in the form of "variants", identified by about 2% nucleotide differences in most genes and 5% in less conserved regions. Less than 100 variants of any HPV type have been detected, a scenario that is very different from the quasi-species formed by many RNA viruses. The variants of each HPV type form phylogenetic trees, and variants from specific branches are often unique to specific ethnic groups. Immigrant populations contain, depending on their respective ethnic origins, mixtures of variants. The absence of HPV genomes intermediate to specific types show that all HPV types existed already when humans became a species. Consequently, humans had always suffered from lesions like anogenital cancer, genital warts and common warts. A growing number of epidemiological, etiological and molecular data suggest that variants of the same HPV type are biologically distinct and may confer differential pathogenic risks. Since the distribution of some variants of HPV-16 and 18 correlates with the distribution of human populations that have an increased risk to develop anogenital cancer, the study of HPV type variation may point to one of the reasons for the higher incidence rates of these lesions in specific cohorts.

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis.

Abstract: Many colorectal tumors lose or downregulate cell surface expression of MHC class I molecules conferring resistance to T-cell-mediated attack. It has been suggested that this phenomenon is due to in vivo immune-tumor interactions. However, evidence of the impact of MHC class I loss on outcomes from colorectal cancer is scarce. In our study of more than 450 colorectal cancers in tissue microarray format, we have shown that both high levels of MHC class I expression and absent MHC class I expression are associated with similar disease-specific survival times, possibly due to natural killer cell-mediated clearance of MHC class I-negative tumor cells. However, tumors with low level expression of MHC class I were found to confer a significantly poorer prognosis, retaining independent significance on multivariate analysis. The existence of these poor prognosis tumors, which may avoid both NK- and T-cell-mediated immune surveillance, has important implications for the design of immunotherapeutic strategies in colorectal cancer.

Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis.

Abstract: Mortalin, also known as mthsp70/GRP75/PBP74, interacts with the tumor suppressor protein p53 and inactivates its transcriptional activation and apoptotic functions. Here, we examined the level of mortalin expression in a large variety of tumor tissues, tumor-derived and in vitro immortalized human cells. It was elevated in many human tumors, and in all of the tumor-derived and in vitro immortalized cells. In human embryonic fibroblasts immortalized with an expression plasmid for hTERT, the telomerase catalytic subunit, with or without human papillomavirus E6 and E7 genes, we found that subclones with spontaneously increased mortalin expression levels became anchorage-independent and acquired the ability to form tumors in nude mice. Furthermore, overexpression of mortalin was sufficient to increase the malignancy of breast carcinoma cells. The study demonstrates that upregulation of mortalin contributes significantly to tumorigenesis, and thus is a good candidate target for cancer therapy.

A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study.

Abstract: The results of prospective studies of the association between dietary salt intake and gastric cancer occurrence remain controversial. To examine this issue in a cohort study of a general population, 2,476 subjects aged 40 years or older were stratified into 4 groups according to the amount of daily salt intake: namely, or = 16.0 per day and were followed up prospectively for 14 years. During the follow-up period, 93 subjects developed gastric cancer. The age- and sex-adjusted incidence was significantly higher in the second to fourth groups than in the first group (age- and sex-adjusted hazard ratio [95% confidence interval], 2.42 [1.24-4.71] for the second group; 2.10 [1.03-4.30] for the third group; 2.98 [1.53-5.82] for the fourth group). This association remained substantially unchanged even after adjusting for other confounding factors such as age, sex, Helicobacter pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes, total cholesterol, physical activity, alcohol intake, smoking habit and other dietary factors. In the stratified analysis, a significant salt-cancer association was observed only in subjects who had both Helicobacter pylori infection and atrophic gastritis (age- and sex-adjusted hazard ratio, 2.87 [1.14-7.24]). Our findings suggest that high dietary salt intake is a significant risk factor for gastric cancer; moreover, this association was found to be strong in the presence of Helicobacter pylori infection with atrophic gastritis.