Showing papers in "International Journal of Cancer in 1998"
TL;DR: The interaction between HBV and HCV infections was negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process.
Abstract: The aim of the study was to assess whether co-infection by hepatitis-B virus (HBV) and hepatitis-C virus (HCV) is associated with a higher risk of developing hepatocellular carcinoma (HCC) than each infection alone. A meta-analysis of data published up to June 1997 was performed. HBsAg and anti-HCV antibodies or HCV RNA (anti-HCV/HCV RNA) were considered as serological markers of current HBV and HCV infection respectively. A total of 32 case-control studies were suitable for a quantitative overview. The summary odds ratios (OR) were 13.7 for HBsAg positivity and 11.5 for anti-HCV/HCV RNA positivity. The OR for anti-HCV was lower among studies using second- or third-generation anti-HCV or HCV RNA (OR, 8.2) with respect to studies with first-generation anti-HCV test (OR, 19.1). When combining data from the studies with second- or third-generation anti-HCV or HCV RNA, the OR for HBsAg positivity and anti-HCV/HCV RNA negativity was 22.5 (95% confidence interval (CI), 19.5-26.0), the OR for anti-HCV/HCV RNA positivity and HBsAg negativity was 17.3 (95% CI, 13.9-21.6), and the OR for both markers positivity was 165 (95% CI: 81.2-374, based on 191 cases and 8 controls exposed). A synergism was found between HBV and HCV infections, the OR for co-infection being greater than the sum and lower than the product of those for each infection alone. The interaction was therefore negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process.
538 citations
TL;DR: The results on colon cancer illustrate both the complexity and the potential of the SEREX approach for analysis of the humoral immune response against human cancer.
Abstract: The screening of cDNA expression libraries derived from human tumors with autologous antibody (SEREX) has proven to be a powerful method for defining the structure of tumor antigens recognized by the humoral immune system. In the present study, 48 distinct antigens (NY-CO-1-NY-CO-48) reactive with autologous IgG were identified by SEREX analysis in 4 patients with colon cancer. Sequencing analysis showed that 17 of the cDNA clones were previously uncharacterized molecules and 31 represented known gene products. The individual cDNA clones were analyzed in the following manner: a search for mutations or other structural changes; an analysis of mRNA expression in a panel of normal tissues; and a frequency analysis of the antibody response to the expressed product in the sera of colon cancer patients and normal individuals. The initial analysis showed NY-CO-13 to be a mutated version of the p53 tumor suppressor gene. Three of the 48 antigens showed a differential pattern of mRNA expression, with NY-CO-27 (galectin-4) expressed primarily in gastrointestinal tract, and NY-CO-37 and -38 showing a pattern of tissue-specific isoforms. With regard to immunogenicity, 20 of the 48 antigens were detected by allogeneic sera; 14 of these were reactive with sera from both normal donors and cancer patients, and 6 other clones (NY-CO-8, -9, -13, -16, -20 and -38) reacted exclusively with sera from colon cancer patients (ranging from 14% to 27%). Our results on colon cancer illustrate both the complexity and the potential of the SEREX approach for analysis of the humoral immune response against human cancer.
391 citations
TL;DR: There was a significant increase in the cumulative incidence of cervical adenocarcinomas in women born in the mid‐1930s and in successive cohorts thereafter in some populations in the United States, Australia, New Zealand, England, Scotland, Denmark, Slovenia, Slovakia and Japan and among Chinese women in Singapore.
Abstract: Time trends in the incidence of cervical adenocarcinoma and adenosquamous cell carcinomas during the period 1973-1991 were examined using data provided by 60 population-based cancer registries from 32 defined populations in 25 countries. Three components of the incidence trend were studied: age, calendar period of diagnosis and birth cohort. Cumulative incidence rates per 1,000 for 2 groups with age ranges 25-49 and 50-74 years were calculated from the model that best described the incidence data. There was a significant increase in the cumulative incidence of cervical adenocarcinomas in women born in the mid-1930s and in successive cohorts thereafter in some populations in the United States (whites and Hispanic women), Australia, New Zealand (non-Maori), England, Scotland, Denmark, Slovenia, Slovakia and Japan (Osaka) and among Chinese women in Singapore, with a general decline in the incidence in women born in earlier periods. In Sweden and Slovenia there is a suggestion of an increasing trend in both age groups. A decrease in incidence in both age groups was apparent in Finland, France and Italy. There were no changes in incidence in 24 registries covering other European, Asian and black populations in the United States. Part of the increase may be attributable to an increasing prevalence of human papillomavirus infection, and part to improvements in screening.
329 citations
TL;DR: Analysis of the breast tumor cell lines indicated that most of the cell lines had the following features: they were derived from large tumors with or without axillary node metastases; were aneuploid and exhibited a moderate to poorly differentiated phenotype; and overexpressed p53 and HER2/neu proteins.
Abstract: The goal of our study was to develop a panel of tumor cell lines along with paired non-malignant cell lines or strains collected from breast cancers, predominantly primary tumors. From a total of 189 breast tumor samples consisting of 177 primary tumors and 12 metastatic tissues, we established 21 human breast tumor cell lines that included 18 cell lines derived from primary tumors and 3 derived from metastatic lesions. Cell lines included those from patients with germline BRCA1 and FHIT gene mutations and others with possible genetic predisposition. For 19 tumor cell lines, we also established one or more corresponding non-malignant cell strains or B lymphoblastoid (BL) lines, which included 16 BL lines and 7 breast epithelial (2) or stromal (5) cell strains. The present report describes clinical, pathological and molecular information regarding the normal and tumor tissue sources along with relevant personal information and familial medical history. Analysis of the breast tumor cell lines indicated that most of the cell lines had the following features: they were derived from large tumors with or without axillary node metastases; were aneuploid and exhibited a moderate to poorly differentiated phenotype; were estrogen receptor (ER)- and progesterone receptor (PR)-negative; and overexpressed p53 and HER2/neu proteins. Of 13 patients with primary breast cancers receiving curative intent mastectomies, 7 were dead after a mean period of 10 months. Our panel of paired tumor and non-malignant cell lines should provide important new reagents for breast cancer research.
323 citations
TL;DR: The results suggest that Hsp27 and Hsp70 are involved in drug resistance in breast cancer patients treated with combination chemotherapies.
Abstract: Heat shock proteins (Hsps) are induced in vitro by several cytotoxic drugs; in human breast cancer cells these proteins appear to be involved in anti-cancer drug resistance. The present report was designed to analyze whether chemotherapy affects in vivo the expression of Hsp27, Hsp70, Hsc70 and Hsp90 in breast cancer patients treated with induction chemotherapy and whether these proteins may be determinants of tumor resistance to drug administration. We have analyzed 35 biopsies from breast cancer patients treated with induction chemotherapy. Expression of the Hsps in the tumors was compared with (i) histological and clinical responses to chemotherapy, (ii) tumor cell proliferation measured by proliferating cell nuclear antigen (PCNA) immunostaining and nucleolar organizer regions (AgNORs) staining and (iii) the expression of estrogen and progesterone receptors. We also compared disease-free survival (DFS) and overall survival (OS) with the expression of the Hsps studied. After chemotherapy, nuclear Hsp27 and Hsp70 expression was increased and Hsp70 and Hsc70 cytoplasmic expression was decreased. A high nuclear proportion of Hsp70 in tumor cells (>10%) correlated significantly with drug resistance. We also observed that patients whose tumors expressed nuclear or a high cytoplasmic proportion (>66%) of Hsp27 had shorter DFS. The combination of Hsp27 and Hsp70 levels showed a strong correlation with DFS. Neither the cellular proliferation nor the levels of steroid receptors showed any significant difference before or after drug administration or during follow-up of patients. Our results suggest that Hsp27 and Hsp70 are involved in drug resistance in breast cancer patients treated with combination chemotherapies.
311 citations
TL;DR: A PSA‐producing and osteoblastic human prostate cancer xenograft model in mice is established and whereas LNCaP cells injected intracardially failed to develop metastasis, C4‐2 cells injected similarly had the highest metastatic capability in SCID/bg mice.
Abstract: LNCaP lineage-derived human prostate cancer cell lines C4-2 and C4-2B4 acquire androgen independence and osseous metastatic potential in vivo. Using C4-2 and C4-2B4 the goals of the current investigation were 1) to establish an ideal bone xenograft model for prostate cancer cells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracardiac administration in athymic or SCID/bg mice. Subsequent to tumor cell administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate-specific antigen (PSA) levels, presence of hematogenous prostate cancer cells and histopathologic evaluation of tumor specimens in the lymph node and skeleton. Our results show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4-2 cells injected similarly had the highest metastatic capability in SCID/bg mice. Retroperitoneal and mediastinal lymph node metastases were noted in 3/7 animals, whereas 2/7 animals developed osteoblastic spine metastases. Intracardiac injection of C4-2 in athymic hosts produced spinal metastases in 1/5 animals at 8-12 weeks post-injection; PC-3 injected intracardially also metastasized to the bone but yielded osteolytic responses. Intravenous injection of either LNCaP or C4-2 failed to establish tumor colonies. Intrailiac injection of C4-2 but not LNCaP nor C4-2B4 cells in athymic mice established rapidly growing tumors in 4/8 animals at 2-7 weeks after inoculation. Intrafemoral injection of C4-2 (9/16) and C4-2B4 (5/18) but not LNCaP (0/13) cells resulted in the development of osteoblastic bone lesions in athymic mice (mean: 6 weeks, range: 3-12 weeks). In SCID/bg mice, intrafemoral injection of LNCaP (6/8), C4-2 (8/8) and C4-2B4 (8/8) cells formed PSA-producing, osteoblastic tumors in the bone marrow space within 3-5 weeks after tumor cell inoculation. A stepwise increase of serum PSA was detected in all animals. Reverse transcription-polymerase chain reaction (RT-PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA level or histological evidence of tumor cells in the marrow space. We have thus established a PSA-producing and osteoblastic human prostate cancer xenograft model in mice.
288 citations
TL;DR: Transmission of Kaposi's sarcoma‐associated herpesvirus in Uganda occurs largely before puberty, in contrast to its sexual mode of transmission among homo/bisexual men and sexually transmitted diseases clinic attendees of Northern Europe and the US.
Abstract: We studied the seroprevalence and transmission of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), among 215 Ugandan children, adolescents and young adults. We measured antibodies to a latent nuclear antigen (LANA) and a lytic cycle protein encoded by open reading frame (orf) 65. Infection with KSHV/HHV8 occurred during early childhood and reached adult levels (approx. 50%) before the age of puberty. In children younger than 12 years of age, antibodies to LANA and the orf65 protein were independently associated with hepatitis B infection (p < 0.005). KSHV/HHV8 infection was not associated with antibodies to hepatitis A virus and hepatitis C virus, nor with the quality of the water supply, household size, previous blood transfusions, number of boy/girl friends or marital status. Antibodies to the orf65 protein, but not LANA, were weakly associated with a history of i.v. injections. Our results show that, in contrast to its sexual mode of transmission among homo/bisexual men and sexually transmitted diseases clinic attendees of Northern Europe and the US, transmission of KSHV in Uganda occurs largely before puberty. Among Ugandan children, KSHV transmission follows a horizontal pattern similar to other herpesviruses, in particular the related γ herpesvirus, Epstein-Barr virus. Transmission of KSHV may be facilitated by living conditions that also promote infection with hepatitis B virus. Int. J. Cancer 77:817–820, 1998.© 1998 Wiley-Liss, Inc.
285 citations
TL;DR: Although NMSC incidence rates continue to rise, there have been reductions in BCC observed in younger age groups, suggesting that public health campaigns to reduce sun exposure may be having a beneficial effect on skin cancer rates.
Abstract: Non-melanocytic skin cancer (NMSC) is the most common cancer in Australia, but data on its incidence are not routinely collected by cancer registries. National surveys were conducted in 1985, 1990 and 1995 to estimate NMSC incidence. Trends in incidence between 1985 and 1995 have been examined to determine the impact of primary prevention campaigns aimed at controlling skin cancer in Australia. National random household surveys of Australians aged over 13 years were used to estimate NMSC incidence in 1985, 1990 and 1995. Age- and sex-specific rates by survey year were modelled using Poisson regression. Basal cell carcinoma (BCC) rates in 1995 were 788 per 100,000, an increase of 19% since 1985. Squamous cell carcinoma (SCC) rates rose by 93% over the same period, from 166 to 321 per 100,000. The ratio of BCC:SCC changed from 4:1 in 1985 to 2.5:1 in 1995. BCC rates in latitudes 37 degrees S over the decade. The ratio of SCC incidence between these latitudes changed from around 7:1 to 3:1 over the same period. Although NMSC incidence rates continue to rise, there have been reductions in BCC observed in younger age groups. Incidence rates of NMSC continue to rise in Australia, but there is evidence of a reduction in BCC incidence in younger cohorts. This is evidence that public health campaigns to reduce sun exposure may be having a beneficial effect on skin cancer rates.
282 citations
TL;DR: Adult‐rat‐brain tissues display an unusually high resistance to necrosis when serially irradiated with parallel, thin slices of a microplanar beam of synchrotron‐wiggler‐generated X rays, and correlation with radiation doses shows that loss of tissue structure was confined to beam‐crossing regions and that only minor damage was done to zones of the brain irradiated unidirectionally.
Abstract: Adult-rat-brain tissues display an unusually high resistance to necrosis when serially irradiated with parallel, thin slices of a microplanar (i.e., microscopically thin and macroscopically broad) beam of synchrotron-wiggler-generated, approx. 35-120 keV (median approx. 50 keV) Gd-filtered X rays at skin-entrance absorbed doses of 312 to 5000 Gy per slice. Such microplanar beams were used to irradiate young adult rats bearing right frontocerebral 9L gliosarcomas (approx. 4 mm diameter), through a volume of tissue containing the tumor and contiguous brain tissue, either in a single array or in 2 orthogonally crossed arrays of tissue slices. Each array included 101 parallel microplanar slices, 100 microm center-to-center distance, each slice being approx. 25 microm wide and 12 mm high, with skin-entrance absorbed doses of 312.5 Gy or 625 Gy per slice. Compared with unirradiated controls with a median survival time of 20 days after tumor initiation, the median survival time was extended in irradiated rats by 139 days (625 Gy, crossed arrays), 96 days (312 Gy, crossed arrays) or 24 days (625 Gy, single array). The tumors disappeared in 22 of the 36 irradiated rats, 4/11 even after unidirectional microbeam irradiation. The extent and severity of radiation damage to the normal brain in rats with or without tumor was graded histopathologically. Correlation of those grades with radiation doses shows that loss of tissue structure was confined to beam-crossing regions and that only minor damage was done to zones of the brain irradiated unidirectionally.
282 citations
TL;DR: The data confirm the role of TIMP‐2 in the down‐regulation of metastasis and angiogenesis but indicate a possible involvement in tumor cell survival.
Abstract: The matrix metalloproteinase (MMP) inhibitor TIMP-2 has a high specificity for gelatinase A/MMP-2. An imbalance between gelatinase A and TIMP-2 in favor of enzymatic activity is linked to the degradation of the extracellular matrix (ECM) associated with several physiologic and pathologic events, including angiogenesis, invasion and metastasis. Since TIMPs are secreted molecules, they have the potential to be used for gene therapy of certain tumors. We transfected B16F10 murine melanoma cells, a highly invasive and metastatic cell line, with an expression vector harboring a cDNA encoding for human TIMP-2. The clones obtained were isolated and examined for TIMP-2 over-expression and changes in tumor cell phenotype. The amount of recombinant TIMP-2 produced correlated with a reduction in invasion. In an in vivo angiogenesis assay, TIMP-2-transfected clones showed reduced levels of blood vessel formation, and in vitro conditioned media from TIMP-2 transfectants showed diminished induction of endothelial cell migration and invasion. TIMP-2 over-expression limited tumor growth in vivo and neoangiogenesis when cells were injected subcutaneously in mice in the presence of Matrigel. However, TIMP-2 over-expressing clones were found to be more resistant to apoptosis than parental and control melanoma cells, while necrosis was increased. Our data confirm the role of TIMP-2 in the down-regulation of metastasis and angiogenesis but indicate a possible involvement in tumor cell survival. Int. J. Cancer 75:246–253, 1998. © 1998 Wiley-Liss, Inc.
277 citations
TL;DR: Using a LAGE‐1 probe to screen a cDNA library from the same melanoma cell line, a closely related gene proved to be identical to NY‐ESO‐1, a gene recently reported to code for an antigen recognized by autologous antibodies in an esophageal squamous cell carcinoma.
Abstract: Representational difference analysis was used to identify genes that are expressed in a human melanoma cell line and not in normal skin. A cDNA clone that appeared to be specific for tumors was obtained and the corresponding gene was sequenced. This new gene was named LAGE-I. Using a LAGE-I probe to screen a cDNA library from the same melanoma cell line, we identified a closely related gene, which proved to be identical to NY-ESO-I, a gene recently reported to code for an antigen recognized by autologous antibodies in an esophageal squamous cell carcinoma. Gene LAGE-I maps to Xq28. It comprises 3 exons. Alternative splicing produces 2 major transcripts encoding polypeptides of 210 and 180 residues, respectively. Expression of LAGE-I was observed in 25-50% of tumor samples of melanomas, non-small-cell lung carcinomas, bladder, prostate and head and neck cancers. The only normal tissue that expressed the gene was testis. As for MAGE-AI, expression of LAGE-I is induced by deoxy-azacytidine in lymphoblastoid cells, suggesting that tumoral expression is due to demethylation. The expression of LAGE-I is strongly correlated with that of NY-ESO-I. It is also clearly correlated with the expression of MAGE genes.
TL;DR: It is proposed that an early step in tumor angiogenesis involves VEGF‐induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.
Abstract: Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.
TL;DR: High pre‐treatment S‐VEGF is associated with poor response to treatment and unfavourable survival in patients with SCLC treated with combination chemotherapy with or without interferon.
Abstract: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability Increased serum VEGF concentrations (S-VEGF) have been found in patients with various types of human cancer, including cancer of the lung However, the clinical and prognostic significance of S-VEGF in cancer is unknown We measured S-VEGF, using enzyme-linked immunosorbent assay, in sera taken from 68 untreated patients with small-cell lung cancer (SCLC) at the time of diagnosis The patients were treated with 6 cycles of cisplatin and etoposide, and were randomly assigned to receive recombinant interferon, leukocyte interferon or neither S-VEGF ranged from 70 to 1738 pg/ml (mean, 527 pg/ml) The patients who achieved partial or complete response to treatment had lower pre-treatment S-VEGF than the non-responding patients (p = 00083, Mann-Whitney test) High (>527 pg/ml) S-VEGF was associated with poor survival (p = 0012, Log Rank Test), and all 3-year survivors had lower than mean pre-treatment S-VEGF In a multivariate analysis, S-VEGF and stage were the only independent prognostic factors, and the estimated 3-year survival of the patients with limited stage disease and low pretreatment S-VEGF (n = 17, 25% of all patients) was 41% (p = 00055, log rank test) These data show that high pretreatment S-VEGF is associated with poor response to treatment and unfavourable survival in patients with SCLC treated with combination chemotherapy with or without interferon
TL;DR: Site‐specific incidence rates demonstrate that highly sun‐exposed body sites are at high risk of developing skin cancer and provide, therefore, strong indirect evidence for the causal relationship between sun exposure and skin cancer.
Abstract: Worldwide, incidence rates of skin cancer are increasing alarmingly in populations of predominantly Caucasian origin A prospective population-based survey, set up to collect epidemiological information on all excised and histologically confirmed skin cancers, started in Townsville, Australia (population of 127,000) in December 1996 Data on the anatomical distribution of skin cancer has been collected using a detailed body map Estimations of type-specific and site-specific incidence rates were age-standardized according to world standard population Site-specific incidence rates were adjusted for surface proportion of the body site and are given per 100,000 body units Between December 1996 and December 1997, a total of 3,536 patients with 5,945 histologically confirmed skin cancer lesions were recorded Age-standardized incidence rates of basal cell carcinoma were 2,0583 for men and 1,1945 for women, 1,3323 for men and 7548 for women for squamous cell carcinoma, and 491 for men and 417 for women for cutaneous melanoma (CM) Site-specific incidence rates of non-melanocytic skin cancer were extreme on sun-exposed areas of the face, whereas site-specific incidence rates of CM were highest for neck, posterior trunk and face Less exposed body sites, such as unexposed upper limbs or thighs, showed reduced incidence rates for all types of skin cancer Tropical North Queensland has the world's highest incidence rates of skin cancer of all types Site-specific incidence rates demonstrate that highly sun-exposed body sites are at high risk of developing skin cancer and provide, therefore, strong indirect evidence for the causal relationship between sun exposure and skin cancer
TL;DR: It was found that increasedmethylation in the E‐cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers, indicating that demethylation of other DNA sequences may predispose to cancer‐promoting chromosomal re‐arrangements.
Abstract: Drug-induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric region instability, facial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocarcinoma. We found that almost half of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromatin adjacent to the centromere of chromosome 1 and is normally highly methylated. One of the 19 examined non-malignant breast tissues displaying fibrocystic changes was similarly hypomethylated in this satellite DNA. We also looked at an opposing type of methylation alteration in these cancers, namely, hypermethylation in a tumorsuppressor gene region that is frequently hypermethylated in breast cancers. We found that increased methylation in the E-cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor-suppressor gene regions may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer-promoting chromosomal re-arrangements. Int. J. Cancer 77:833‐838, 1998. r 1998 Wiley-Liss, Inc.
TL;DR: It is suggested that sun exposure during childhood and during adulthood would be interdependent as far as their impact on melanoma risk is concerned, andSun avoidance during childhood would have a greater impact on sun exposure than sun avoidance during adulthood.
Abstract: Sun exposure in both childhood and adult life represents the main environmental risk determinant for cutaneous melanoma. However, little is known about the joint effects of sun exposure during early and later life on melanoma risk. A case-control study in Belgium, Germany and France conducted in 1991-1992 suggests that the melanoma risks attached to indicators related to sun exposure appear to combine their effects in an additive way. We therefore constructed composite indices of sun exposure during childhood and during adulthood, assuming additive combinations of melanoma risk associated with each indicator of sun exposure. Logistic regression modeling showed that the melanoma risk associated with a given level of sun exposure during adulthood increased with higher sun exposure during childhood, but the increase in risk was higher than the simple addition of melanoma risk associated with sun exposure during childhood or adulthood. In turn, high sun exposure during childhood constituted a significant risk factor for melanoma only if there was substantial sun exposure during adult life. We thus suggest that sun exposure during childhood and during adulthood would be interdependent as far as their impact on melanoma risk is concerned. Our results support the hypothesis by which the important contribution of sun exposure during childhood in melanoma occurrence is not properly assessed by retrospective epidemiologic studies. Sun avoidance during childhood would have a greater impact on melanoma risk than sun avoidance during adulthood.
TL;DR: In this article, a kinetic quantitative polymerase-chain reaction (PCR) method, based on fluorescent TaqMan methodology and a new instrument (ABI Prism 7700 Sequence Detection System) capable of measuring fluorescence in real-time, was used to quantify gene amplification in tumor DNA.
Abstract: Gene amplification is a common event in the progression of human cancers, and amplified oncogenes have been shown to have diagnostic, prognostic and therapeutic relevance. A kinetic quantitative polymerase-chain-reaction (PCR) method, based on fluorescent TaqMan methodology and a new instrument (ABI Prism 7700 Sequence Detection System) capable of measuring fluorescence in real-time, was used to quantify gene amplification in tumor DNA. Reactions are characterized by the point during cycling when PCR amplification is still in the exponential phase, rather than the amount of PCR product accumulated after a fixed number of cycles. None of the reaction components is limited during the exponential phase, meaning that values are highly reproducible in reactions starting with the same copy number. This greatly improves the precision of DNA quantification. Moreover, real-time PCR does not require post-PCR sample handling, thereby preventing potential PCR-product carry-over contamination; it possesses a wide dynamic range of quantification and results in much faster and higher sample throughput. The real-time PCR method, was used to develop and validate a simple and rapid assay for the detection and quantification of the 3 most frequently amplified genes (myc, ccndl and erbB2) in breast tumors. Extra copies of myc, ccndl and erbB2 were observed in 10, 23 and 15%, respectively, of 108 breast-tumor DNA; the largest observed numbers of gene copies were 4.6, 18.6 and 15.1, respectively. These results correlated well with those of Southern blotting. The use of this new semi-automated technique will make molecular analysis of human cancers simpler and more reliable, and should find broad applications in clinical and research settings.
TL;DR: The consistency of the patterns observed indicate that, in this population, higher frequency of whole grain food intake is an indicator of reduced risk of several neoplasm at all sites, except thyroid.
Abstract: The relationship between frequency of consumption of whole grain food and risk of selected neoplasms has been analysed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1996. The overall dataset included the following incident, histologically confirmed neoplasms: oral cavity and pharynx 181, oesophagus 316, stomach 745, colon 828, rectum 498, liver 428, gallbladder 60, pancreas 362, larynx 242, breast 3,412, endometrium 750, ovary 971, prostate 127, bladder 431, kidney 190, thyroid 208, Hodgkin's disease 80, non-Hodgkin's lymphomas 200, multiple myelomas 120. Controls were 7,990 patients admitted to hospital for acute, non-neoplastic conditions, unrelated to long-term modifications in diet and not likely to have been caused by tobacco or alcohol use. Odds ratios (OR) for subsequent scores (never/occasional/frequent) of whole grain food consumption were derived after allowance for age, sex, education, smoking, alcohol intake and body mass index. High intake of whole grain foods consistently reduced risk of neoplasm at all sites, except thyroid. The ORs for the highest category of consumption were 0.2–0.3 for upper digestive and respiratory tract neoplasms, 0.5 for stomach, colon and gallbladder, 0.7 for rectum, 0.6 for liver, 0.8 for pancreas and prostate, 0.9 for breast and endometrium, 0.6 for ovary, 0.4 for bladder and kidney, 1.3 for thyroid and around 0.5 for lymphomas and myeloma. The tests for trend in risks were significant for all neoplasms, except pancreas, endometrium, Hodgkin's disease and multiple myeloma. No significant heterogeneity was found across strata of age at diagnosis, sex, education, smoking habit, alcohol intake and body mass index. Thus, even in the absence of a univocal and satisfactory biological interpretation, the consistency of the patterns observed indicate that, in this population, higher frequency of whole grain food intake is an indicator of reduced risk of several neoplasms. Int. J. Cancer 77:24–28, 1998.© 1998 Wiley-Liss, Inc.
TL;DR: A strain survey was initiated utilizing a transgenic mouse mammary tumor model that exhibits a high incidence of pulmonary metastases, and 13 strains were identified that had a statistically significant reduction in the numbers ofmonary metastases.
Abstract: Metastasis is one of the most important and complex processes in human neoplastic disease. A large number of both positive and negative events must occur to permit a tumor cell to colonize a distant site successfully. To identify mouse strains that harbor dominant genetic modifiers of this process, a strain survey was initiated utilizing a transgenic mouse mammary tumor model that exhibits a high incidence of pulmonary metastases. The transgenic animal was bred to 27 different inbred strains of mice and scored for the metastatic organ tropism and metastatic density. Thirteen strains were identified that had a statistically significant reduction in the numbers of pulmonary metastases. In addition, 10 strains were identified that altered the kinetics of induction of the primary mammary tumor. These strains will likely provide useful model systems for the analysis of genetic interactions in the initiation and progression of mammary adenocarcinomas.
TL;DR: The results of this pilot study suggest that the ability of breast cancer cells to either synthesize OPN or to bind and sequester OPN from the microenvironment may be associated with tumor aggressiveness and poor prognosis.
Abstract: The aim of this study was to examine the cellular distribution of osteopontin (OPN) protein [by immunohistochemical (IHC) analysis] and mRNA [by in situ hybridization (ISH)] in the primary tumors of lymph node negative (LNN) breast cancer patients and to determine whether the level of immunodetectable OPN may be associated with tumor aggressiveness. We examined OPN levels in tumors from 154 patients with LNN breast cancer who were followed for a median of 7 years (range 1.7-16.3 years). IHC staining for OPN was seen in tumor infiltrating macrophages and lymphocytes in 70% of these tumors, and in the carcinoma cells themselves in 26%. ISH was performed to determine cellular distribution of OPN mRNA expression in sections from selected tumors. OPN mRNA was detected in groups of tumor cells, individual tumor cells and tumor infiltrating macrophages and lymphocytes. Matched sections showed that some tumor cells with IHC staining for OPN protein were also positive for OPN mRNA by ISH, in contrast with previous studies which have shown OPN mRNA expression only in tumor infiltrating inflammatory cells. Our results thus indicate that OPN protein can be produced by breast cancer cells in vivo and suggest that it may also be taken up from the environment (i.e., secreted by inflammatory cells or other tumor cells). Tumor cell IHC staining intensity was then assessed using a semiquantitative scoring system. Univariate analysis showed tumor cell OPN positivity above an optimized cutpoint to be significantly associated with decreased disease-free survival (DFS) and overall survival (OS). The results of this pilot study thus suggest that the ability of breast cancer cells to either synthesize OPN or to bind and sequester OPN from the microenvironment may be associated with tumor aggressiveness and poor prognosis.
TL;DR: The findings have important implications, suggesting weight preservation as a means for prevention of post‐menopausal breast cancer as well as a causal role of childhood body build in breast cancer etiology.
Abstract: Adult obesity has been associated with an increased risk of post-menopausal breast cancer, but it is unclear whether this relationship reflects a causal role of obesity during childhood and adolescence, of weight gain during adult life or of adult obesity per se. In a population-based case-control study in all of Sweden, we included 3,345 (84% of all eligible) women aged 50-74 years with invasive breast cancer, and 3,454 (82% of all selected) controls of similar age. Mailed questionnaires and telephone interviews were used to collect detailed information on anthropometric measures. Odds ratios were estimated through multiple logistic regression. Women with the leanest somatotype at age 7 had about a 3-fold higher risk of breast cancer than the most obese (P for trend 0.0009). A suggested protective effect of a high body mass at age 18 and a detrimental influence of body mass 1 year prior to data collection largely reflected the effect of weight gain after age 18, a strong predictor of breast cancer risk. Among women at least 20 years post menopause, those who had gained 30 kg or more since age 18 had an odds ratio of 2.04 (95% confidence interval 1.20-3.48) of breast cancer compared with those who had maintained their weight unchanged. The effect of weight gain was unequivocal among non-users but not among users of hormone replacement therapy. Our findings have important implications, suggesting weight preservation as a means for prevention of post-menopausal breast cancer as well as a causal role of childhood body build in breast cancer etiology.
TL;DR: The most favourable diet for oral cancer risk is given by infrequent consumption of red and processed meat and eggs and, most of all, frequent vegetable and fruit intake.
Abstract: The role of specific food groups and diet variety on the risk of oral and pharyngeal cancer has been considered using data from a case-control study conducted between 1992 and 1997 in the Swiss Canton of Vaud. Cases were 156 patients (126 males, 30 females) aged under 75 (median age 56) years with incident, histologically confirmed cancer of the oral cavity and pharynx, and controls were 284 subjects (246 males, 38 females, median age 57 years), admitted to the same university hospital for a wide spectrum of acute, non-neoplastic conditions unrelated to tobacco and alcohol consumption or to long-term modification of diet. After allowance for education, alcohol, tobacco and total energy intake, significant trends of increasing risk with more frequent intake emerged for eggs (OR = 2.3 for the highest tertile), red meat (OR = 2.1) and pork and processed meat (OR = 3.2). Inverse trends in risk were observed for milk (OR = 0.4 for the highest tertile), fish (OR = 0.5), raw vegetables (OR = 0.3), cooked vegetables (OR = 0.1), citrus fruit (OR = 0.4) and other fruits (OR = 0.2). The addition of a serving per day of fruit or vegetables was associated with an about 50% reduction in oral cancer risk. The most favourable diet for oral cancer risk is therefore given by infrequent consumption of red and processed meat and eggs and, most of all, frequent vegetable and fruit intake. Diet diversity was inversely related to oral and pharyngeal cancer: ORs were 0.35 for the highest tertile of total diversity, 0.24 for vegetable and 0.34 for fruit diversity. In terms of attributable risk, high meat intake accounted for 49% of oral and pharyngeal cancers in this population, low vegetable intake for 65% and low fruit intake for 54%.
TL;DR: Results indicate that hyaluronan oligomers injected at concentrations as low as 1 mg/ml can markedly inhibit B16F10 melanoma growth, providing a potentially attractive reagent for the control of local tumor development.
Abstract: One of the critical events in tumor growth and metastasis is the interaction between tumor cells and host tissue stroma, mediated by different adhesion receptor repertoires in different tumor cell types. Several lines of evidence indicate that interaction between the hyaluronan receptor CD44, expressed on tumor cells, and host tissue stromal hyaluronan can enhance growth and invasiveness of certain tumors. Disruption of CD44-hyaluronan interaction by soluble recombinant CD44 has been shown to inhibit tumor formation by lymphoma and melanoma cells transfected with CD44. Since hyaluronan is a ubiquitous glycosaminoglycan polymer from which oligosaccharides of defined size can be readily purified, we tested the ability of hyaluronan oligomers to inhibit tumor formation by subcutaneously (s.c.) injected B16F10 melanoma cells. Our results indicate that hyaluronan oligomers injected at concentrations as low as 1 mg/ml can markedly inhibit B16F10 melanoma growth, providing a potentially attractive reagent for the control of local tumor development.
TL;DR: The overall role of GST polymorphisms in modifying the lung cancer risk may be more limited than has been so far anticipated.
Abstract: Glutathione S-transferases (GSTs) are known to take part in detoxification of many potentially carcinogenic compounds Therefore, polymorphisms of the GST genes have been considered as potentially important modifiers of individual risk of environmentally induced cancers The association between lack of glutathione S-transferase M1 gene (GSTM1 null genotype) and susceptibility to smoking-related lung cancer has been actively studied, with contradictory results In contrast, little is known about the more recently found polymorphisms in GSTM3, GSTP1 and GSTT1 genes with respect to individual responses to environmental exposures In this study, we determined the genotype distribution of all these genes, and their combinations, among 208 Finnish lung cancer patients and 294 population controls None of the genotypes studied had a statistically significant effect on lung cancer risk, when studied separately However, a significant association was observed for concurrent lack of the GSTM1 and GSTT1 genes and susceptibility to squamous cell carcinoma For that cell type, the risk was more than 2-fold when compared with that of individuals having other genotype combinations (OR = 23; 95% CI = 10–53; p = 005) Moreover, the risk was mostly attributable to patients with smoking history of 40 pack-years or less (OR = 29; 95% CI = 11–77; p = 003) In contrast, this genotype combination did not affect the risk for other histological types of lung cancer, and the other genotype combinations had no effects on individual susceptibility to this malignancy The overall role of GST polymorphisms in modifying the lung cancer risk may therefore be more limited than has been so far anticipated Int J Cancer 77:516–521, 1998 © 1998 Wiley-Liss, Inc
TL;DR: Ets‐1 and Ets‐2 provide the link connecting EGF stimuli with activation of uPA and 92 kDa type IV collagenase promoters and may contribute to invasion phenotypes.
Abstract: Urokinase plasminogen activator (uPA) has been associated with invasion and metastasis in breast cancer. The expression of uPA and 92 kDa type IV collagenase (gelatinase B/MMP-9) is regulated by growth factors, receptor-type tyrosine kinases and cytoplasmic oncoproteins. Here, we have identified transcriptional requirements for the induction of uPA and 92 kDa type IV collagenase by epidermal growth factor (EGF). EGF stimulates the motile and invasive activities specifically in the ErbB-2-overexpressing SK-BR-3 cells. Expression of extracellular matrix-degrading proteases including type I collagenase/MMP-1, 92 kDa type IV collagenase/MMP-9, uPA and uPA receptor were induced. EGF also transiently stimulated expression of the transcription factors Ets-1 and Ets-2. Reporter transfection assays revealed the activation of uPA and MMP-9 collagenase promoters by EGF and the requirement of each of the composite Ets and AP-1 transcription factor binding sites for an EGF response. Most notably, transfections with the Ets-1 and Ets-2 expression vectors potentiated uPA and MMP-9 promoter activation in response to EGF. Mutation of the threonine 75 residue of chicken Ets-2 conserved in the Pointed group of the Ets family proteins abrogated the ability of Ets-2 to collaborate with EGF. Ets-1 and Ets-2 were highly expressed in invasive breast tumor cell lines. Our results suggest that Ets-1 and Ets-2 provide the link connecting EGF stimuli with activation of uPA and 92 kDa type IV collagenase promoters and may contribute to invasion phenotypes.
TL;DR: A multivariate analysis suggested that the most important risk factors were beer and liquor consumption, followed by smoking, followedBy smoking, which showed the strongest risk for oral cancer.
Abstract: The use of oral snuff is a widespread habit in Sweden. We investigated whether the use of Swedish moist snuff leads to an increasing risk of oral cancer. Other risk factors such as smoking tobacco and alcoholic beverages were also investigated. Our study comprised 410 patients with oral cancer, from the period 1980-1989, and 410 matched controls. All subjects received a mailed questionnaire. The response rates were 96% and 91% for cases and controls, respectively. In the study, a total of 20% of all subjects, cases and controls, were active or ex-snuff users. The univariate analysis did not show any increased risk [odds ratio (OR) 0.7, 95% confidence interval (CI) 0.4-1.1] for active snuff users. We found an increased risk (OR 1.8, CI 1.1-2.7) for oral cancer among active smokers. Alcohol consumption showed the strongest risk for oral cancer. Among consumers of beer, an increased risk of 1.9 (CI 0.9-3.9) was found. Corresponding ORs for wine and liquor were 1.3 (CI 0.9-1.8) and 1.6 (CI 1.1-2.3), respectively. A dose-response effect was observed. Although not statistically significant, a multivariate analysis similarly suggested that the most important risk factors were beer and liquor consumption, followed by smoking.
TL;DR: The findings show that Trop‐2 transduces an intracellular calcium signal, are consistent with the hypothesis that it acts as a cell surface receptor and support a search for a physiological ligand.
Abstract: Trop-2/EGP-1/GA733-1 is a recently identified cell surface glycoprotein highly expressed by human carcinomas. The cytoplasmic tail of Trop-2 possesses potential serine and tyrosine phosphorylation sites and a phosphatidyl-inositol binding consensus sequence. Thus, we investigated whether Trop-2 might be a functional signaling molecule. Using the fluorescent probe Fura-2, we assayed the cytoplasmic calcium levels in human cancer cells stimulated with anti-Trop-2 or control antibodies. Three anti-Trop-2 MAbs, Rs7-7G11, MOv16 and 162-46.2 specifically induced a transient intracellular calcium level increment in up to 40% of the experiments performed. Polyclonal antisera recognizing recombinant Trop-2 molecules possessed a much lower stimulation efficiency. The average latency of antibody-induced Ca2+ rise for OvCa-432 cells was 64+/-26 sec. Internal Ca2+ concentrations reached peaks of 190+/-24 nM vs. basal levels of 61+/-4 nM and returned to baseline within 193+/-37 sec. Similar values were obtained in MCF-7 cells. For comparison, stimulation of P2-purinergic receptors on MCF-7 and OvCa-432 cells induced a Ca2+ rise in most cases, leading to average internal Ca2+ concentrations of 297+/-41 and 391+/-39 nM, respectively. Our findings show that Trop-2 transduces an intracellular calcium signal, are consistent with the hypothesis that it acts as a cell surface receptor and support a search for a physiological ligand.
TL;DR: The association of diet, smoking/drinking and occupation with subsequent risk of fatal colorectal cancer was investigated in a cohort of white males aged 35 and older and support previous reports that a high intake of red meat and a sedentary life‐style may increase the risk of colon cancer.
Abstract: The association of diet, smoking/drinking and occupation with subsequent risk of fatal colorectal cancer was investigated in a cohort of 17,633 white males aged 35 and older, who completed a mail questionnaire in 1966. During the subsequent 20 years of follow-up, 120 colon cancer and 25 rectal cancer deaths were identified. Due to small numbers, no significant dose-response trends were observed in the study, but risk of colon cancer was elevated among heavy cigarette smokers (> or = 30/day; RR = 2.3, 95% CI 0.9-5.7), heavy beer drinkers (> or = 14 times/month; RR = 1.9, 95% CI 1.0-3.8) and white-collar workers (RR = 1.7, 95% CI 1.0-3.0) or crafts workers within service and trade industries (RR = 2.6, 95% CI 1.1-5.8). In addition, an increased risk was seen for those who consumed red meat more than twice a day (RR = 1.8, 95% CI 0.8-4.4). Risk patterns for cancers of the colon and rectum combined were similar to those reported for cancer of the colon, but the estimates were somewhat dampened. Our findings support previous reports that a high intake of red meat and a sedentary life-style may increase the risk of colon cancer.
TL;DR: KSHV/HHV‐8 appears to be sexually transmitted, probably by receptive anal intercourse, and may have been introduced to Danish homosexual men via sex with US men and by the same activities that lead to the spread of HIV.
Abstract: A newly identified herpesvirus has been associated with Kaposi's sarcoma. We determined risk factors for Kaposi's-sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) seropositivity and incidence of infection over time in a cohort of Danish homosexual men followed from 1981 to 1996. Antibodies to a latent nuclear (LANA) and a structural (orf65) antigen of KSHV/HHV-8 were measured by immunofluorescence and ELISA/WB respectively. Through linkage with the national AIDS registry, all cohort members diagnosed with AIDS as of September 1996 were identified and their hospital records were scrutinized to record all diagnoses of KS. Overall, 21.1% (52/246) of the men were KSHV/HHV-8-seropositive in 1981. Among the initially seronegative, the rate of KSHV/HHV-8 seroconversion was highest between 1981 and 1982 and declined steadily thereafter. In a multivariate analysis of the status at enrollment in 1981, KSHV/HHV-8 seropositivity was not associated with age but was independently associated both with number of receptive anal intercourses (OR = 2.83; p = 0.03) and with sex with US men (OR = 2.27; p < 0.05). In a multivariate analysis of follow-up data, risk of KSHV/HHV-8 seroconversion was independently associated with having visited homosexual communities in the United States, and current HIV-positive status. More than 5 years' homosexual experience was associated with an insignificantly increased risk (RR = 2.68). KS occurred only in HIV-positive men who were KSHV/HHV-8-positive at or prior to their KS diagnosis. In conclusion, KSHV/HHV-8 appears to be sexually transmitted, probably by receptive anal intercourse, and may have been introduced to Danish homosexual men via sex with US men. The epidemic of KSHV/HHV-8 is now declining. These findings are concordant with the view that KSHV/HHV-8 may have been actively spread simultaneously with and by the same activities that lead to the spread of HIV.
TL;DR: The results suggest that overexpression of OPN correlated with the progression of human gastric carcinoma, and interaction between OPN and CD44 may parallel lymphogenous metastasis in CD44‐bearing poorly differentiated gastric cancer.
Abstract: We have examined the expression of osteopontin (OPN) in 40 human primary gastric carcinoma tissues, 5 metastatic foci (lymph nodes) and corresponding normal mucosas. Twenty-nine of 40 primary tumors (72.5%) and 3 of 5 lymph node metastases (60%) overexpressed OPN mRNA in comparison with those of the corresponding normal mucosa. The incidence as well as relative expression level of OPN mRNA was higher in well differentiated gastric cancers than poorly differentiated ones. Moreover, increased OPN mRNA expression in primary tumor specimens was observed along with the advancement of the clinico-pathological stage. Using in situ hybridization (ISH) analysis, not only inflammatory cells in tumor stroma but also tumor cells showed positive signals for OPN mRNA. By immunohistochemistry, co-immunoreaction of OPN and CD44v9 in tumor cells obviously correlated with the degree of lymphatic vessel invasion or long distant lymph node metastases in poorly differentiated gastric cancer. Interestingly, strong co-immunoreaction of OPN and CD44v9 of tumor cells was concommitant with cluster formation in the lymphatic vessels. Our results suggest that overexpression of OPN correlated with the progression of human gastric carcinoma. Especially in CD44-bearing poorly differentiated gastric cancer, interaction between OPN and CD44 may parallel lymphogenous metastasis.