Is early diagnosis of pancreatic cancer fiction? Surveillance of individuals at high risk for pancreatic cancer

Pancreatic cancer represents one of the most deadly human malignancies with an overall 5-year survival of less than 5%. Despite improvements in imaging techniques and surgical techniques, survival statistics have hardly improved over the past decades. To improve the dismal outlook it would be highly desirable to develop a program to detect precursor lesions or small asymptomatic early cancers at the time when the disease is still at a curable stage. Screening the general population for disease presence is not feasible at present because of the relatively low disease incidence and the lack of a noninvasive, reliable and cheap screening tool. Targeted surveillance programs, however, in individuals at high risk for developing pancreatic cancer, like mutation carriers of pancreatic cancer prone hereditary (tumor) syndromes or individuals with a strong family history of pancreatic cancer without a known underlying genetic defect, might be feasible. Careful consideration of the criteria put forward by Wilson and Jungner as published by the World Health Organization on the principles and practice of screening for disease, indicate that surveillance in this high-risk population by means of endosonography (EUS) and/or magnetic resonance imaging (MRI) represents a promising development, though experimental. It nicely points out which open questions need to be addressed. Among others, these include how to acquire a better understanding of the natural behavior and progression of precursor lesions towards invasive cancer, how to firmly establish the performance characteristics of EUS and MRI for the detection of (early) lesions in individuals at high risk for pancreatic cancer, and how to determine which lesions can be safely observed with continued surveillance and which lesions justify resection.     

Expression of Survivin in pancreatic cancer and its correlation to expression of Bcl-2

AIM:To investigate the expression of Survivin in pancreaticcancer and its correlation to the expression of Bcl-2.METHODS:Survivin and Bcl-2 expressions were examinedby immunohistochemistry in 42 tissue samples frompancreatic cancer and 10 from normal pancrease.RESULTS:No survivin expression was detected in the tissuesamples from normal pancrease,while it was detected in34 of 42 tissue samples from pancreatic cancer (81.95%).There was a correlation between survivin expression anddifferentiation and stages of pancreatic cancer.Survivinpositive cases were strongly correlated to Bcl-2 expression(28/30 vs6/12,P<0.05).CONCLUSION:Overexpression of survivin plays animportant role in the development and progression ofpancreatic cancer,and correlates to the expression of Bcl-2.Survivin expression can be used as a prognostic factor.     

K-ras mutation status correlates with the expression of VEGFR1, VEGFR2, and PDGFRα in colorectal cancer

Aim  

We initiated this study in order to analyze whether the expression level of targeted receptor tyrosine kinases (RTK) is associated with the K-ras mutation status.     

β-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: Relationships with carcinogenesis and metastasis

AIM: To investigate whether abnormal expression of β-catenin in conjunction with overexpression of cyclinD1, c-myc and matrix metalloproteinase-7 (MMP-7) correlated with the carcinogenesis, metastasis and prognosis of pancreatic cancer, and to analyze the relationship of β-catenin expression with cyclinDl, c-myc and MMP-7 expression. METHODS: Using immunohistochemistry,we examined the expression of β-catenin, cyclinD1,c-myc and MMP-7 in 47 pancreatic adenocarcinoma tissues, 12 pancreatic intraepithelial neoplasia (PanIN) and 10 normal pancreases, respectively. Proliferation cell nuclear antigen was also tested as the index of proliferative activity of pancreatic cancer cells. RESULTS: In 10 cases of normal pancreatic tissues, epithelial cells showed equally strong membranous expression of β-catenin protein at the cell-cell boundaries, but the expression of cyclinDl, c-myc and MMP-7 was negative. The expression of β-catenin, cyclinD1, c-myc and MMP-7 in PanIN and pancreatic adenocarcinoma tissues had no significant difference [6/12 and 32/47 (68.1%), 6/12 and 35/47 (74.5%), 5/12 and 33/47 (70.2%), 7/12 and 30/47 (63.8%), respectively]. The abnormal expression of β-catenin was significantly correlated to metastasis and one-year survival rate of pancreatic cancer, but had no relation with size, differentiation and cell proliferation. The expression of cyclinD1 was correlated with cell proliferation and extent of differentiation, but not with size, metastasis and one-year survival rate of the pancreatic cancer. The expression of c-myc was not correlated with size, extent of differentiation, metastasis and 1-year survival rate, but closely with cell proliferation of pancreatic cancer. The overexpression of MMP-7 was significantly associated with metastasis and 1-year survival rate of pancreatic cancer,but not with size, extent of differentiation and cell proliferation.There was a highly significant positive association between abnormal expression of β-catenin and overexpression of cyclinD1, c-myc and MMP-7 not only in PanIN (r= 1.000, 0.845, 0.845), but also in pancreatic cancer (r= 0.437, 0.452, 0.435). CONCLUSION: The abnormal expression of β-catenin plays a key role in the carcinogenesis and progression of human pancreatic carcinoma by up-regulating the expression of cyclinDl, c-myc and MMP-7, resulting in the degradation of extracellular matrix and uncontrolled cell proliferation and differentiation,β-catenin abnormal expression and MMP-7 overexpression may be considered as two useful markers for determining metastasis and prognosis of human pancreatic cancer.     

Induction of HSF1 expression is associated with sporadic colorectal cancer

AIM:To explore the activation of signal transduction pathwaysrelated with the carcinogenesis of sporadic colon cancers.METHODS:A gene array monitoring the activation of 8 signaltransduction pathways(PathwayFinder GEArray)was usedto screen the differentially expressed genes betweencolorectal cancer and normal colon tissues.The differentiallyexpressed genes were further analyzed by RT-PCR,usingRNA derived from colorectal cancer and normal colon tissueof 35 patients.RESULTS:The expression of HSF1,HSF27,HSP90 and iNOSwas increased in colon cancer tissues compared to normalcolon tissue using PathwayFinder GEArray.The RT-PCRresults showed that the expression of HSF1 was increasedin 86%(30/35)patients and the expression of iNOS wasincreased in 63%(22/35)patients.CONCLUSION:The induction of HSF1 gene expression isassociated with sporadic colon cancer.HSF1 induces heatshock stress signaling pathway,which might play a role inthe carcinogenesis of sporadic colorectal cancer.Cen H,Zheng S,Fang YM,Tang XP,Dong Q.Induction ofHSF1 expression is associated with sporadic colorectal cancer.World J Gastroenterol 2004;10(21):3122-3126http://www.wjgnet.com/1007-9327/10/3122.asp     

Molecular biology of Barrett's esophagus and esophageal cancer:role of p53

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Evaluation of VEGF and VEGF-C expression in gastric cancer cells producing α-fetoprotein

Background. Gastric cancers producing α-fetoprotein (AFP) are known to have a poor prognosis and to show a high incidence of liver metastasis. Vascular endothelial growth factor (VEGF) and its isoform VEGF-C are reported to be associated with tumor progression through an angiogenic or lymphangiogenic function. In the present study, to clarify the cellular characteristics of AFP-producing gastric cancers, the expression of VEGF and that of VEGF-C in AFP-producing gastric cancer was compared with their expression in gastric cancers that do not produce AFP. Methods. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients with stage-matched gastric cancers that did not produce AFP [AFP(−)] were evaluated for VEGF and VEGF-C expression and vessel density, using immunohistochemical analysis. Results. The survival rate of the AFP(+) group was significantly worse than that of the stage-matched AFP(−) group (P < 0.05). The frequency of VEGF-C expression was significantly higher in the AFP(+) group than in the AFP(−) group (P < 0.01). There was no significant difference in VEGF expression between the AFP(+) and AFP(+) groups. The microvessel density was higher in the AFP(+) group than in the AFP(−) group (P < 0.05). Conclusions. A higher expression of VEGF-C might be one explanation for the poorer prognosis of AFP-producing gastric cancers. Received: June 7, 2002 / Accepted: October 25, 2002 RID="*" ID="*" Reprint requests to: K. Kono     

Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: A meta-analysis

Background and aimsPancreatic cancer is characterized by inadequate vascularization and considerable tumor hypoxia is prevalent. However, whether hypoxia-inducible factor 1α (HIF-1α) is significantly correlated with clinical prognosis in pancreatic cancer remains unclear. We aimed to determine the value of HIF-1α as a predictor of survival in pancreatic cancer through a meta-analysis of available cohort studies.MethodsWe performed a literature search of the MEDLINE, Embase, and Cochrane Library databases to identify cohort studies on the prognostic value of HIF-1α in pancreatic cancer. We conducted a meta-analysis to examine the clinical status and overall survival of patients with high HIF-1α expression compared to those with low expression.ResultsWe analyzed eight studies involving 557 patients. HIF-1α was associated with higher rate of lymph node metastasis (odd ratio [OR] = 3.16; 95% confidence interval [CI] = 1.95–5.11; p < 0.05) and advanced tumor stage (OR = 3.66; 95% CI = 2.01–6.69; p < 0.05), while no significant difference was detected for tumor diameter (OR = 1.58; 95% CI = 0.46–5.47; p > 0.05). Notably, HIF-1α overexpression was significantly correlated with poor overall survival (hazard ratio [HR] = 1.88; 95% CI = 1.39–2.56; p < 0.05).ConclusionsWe believe that HIF-1α overexpression is significantly associated with poor prognosis in pancreatic cancer, and may serve as an important parameter for evaluating the biological behavior and prognosis of pancreatic cancer.     

Effects of interferon-alpha on expression of hepatic stellate cell and transforming growth factor-β1 and α-smooth muscle actin in rats with hepatic fibrosis

AIM: To investigate the effect of interferon-α(IFN-α) on preventing or reversing hepatic fibrosis in rat experimental model induced by CCl4.METHODS: One hundred and ten Sprague-Dawley rats were divided into five groups: group A (normal controls,n=18), group B (fibrotic model controls, n=22), group C (IFN-α prevention, n=22) initially treated with intra-muscular injection of IFN-α in saline daily at the doses of 1&#215;105U for 6wk, group D (IFN-α treatment, n=24) treated with intra-muscular injection of IFN-α in saline daily at the doses of 1&#215;105U for 6wk after the first 6wk, group E (0.9% sodium chloride treatment control, n=24) treated with intra-muscular injection of 0.01mL/kg daily for 6wk after the first 6wk. At the end of the experiment, all rats of each group were killed. Samples of the liver obtained by biopsy were subjected to histological, immunohistochemical and electron microscopic studies for the expressions of transforming growth factor-β1(TGF-β1) and α-smooth muscle actin (α-SMA).RESULTS: The expressions of TGF-β1, the number of activated hepatic stellate cells and α-SMA in hepatic tissue of group C were significantly less than those of group B(P&lt;0.01). The degree of fibrosis score in group B was also significantly less than that of group C under light microscope (P&lt;0.01).CONCLUSION: IFN-α can inhibit the production of TGF-β1, decrease HSC activation and stimulate its apoptosis.     

Optogenetic control of insulin secretion in intact pancreatic islets with β-cell-specific expression of Channelrhodopsin-2

Insulin is secreted from the pancreatic β-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of β-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of β-cells in intact islets. We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter. Glucose tolerance in vivo was assessed using intraperitoneal glucose tolerance tests, and glucose-induced insulin release was measured from static batch incubations. ChR2 localization was determined by fluorescence confocal microscopy. The effect of ChR2 stimulation with blue LED light was assessed using Ca²⁺ imaging and static islet incubations. Light stimulation of islets from transgenic ChR2 mice triggered prompt increases in intracellular Ca²⁺. Moreover, light stimulation enhanced insulin secretion in batch-incubated islets at low and intermediate but not at high glucose concentrations. Glucagon release was not affected. Beta-cells from mice rendered diabetic on a high-fat diet exhibited a 3.5-fold increase in light-induced Ca²⁺ influx compared with mice on a control diet. Furthermore, light enhanced insulin release also at high glucose in these mice, suggesting that high-fat feeding leads to a compensatory potentiation of the Ca²⁺ response in β-cells. The results demonstrate the usefulness and versatility of optogenetics for studying mechanisms of perturbed hormone secretion in diabetes with high time-resolution and cell-specificity.     

Optogenetic control of insulin secretion in intact pancreatic islets with β-cell-specific expression of Channelrhodopsin-2

Insulin is secreted from the pancreatic β-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of β-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of β-cells in intact islets.

We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter. Glucose tolerance in vivo was assessed using intraperitoneal glucose tolerance tests, and glucose-induced insulin release was measured from static batch incubations. ChR2 localization was determined by fluorescence confocal microscopy. The effect of ChR2 stimulation with blue LED light was assessed using Ca²⁺ imaging and static islet incubations.

Light stimulation of islets from transgenic ChR2 mice triggered prompt increases in intracellular Ca²⁺. Moreover, light stimulation enhanced insulin secretion in batch-incubated islets at low and intermediate but not at high glucose concentrations. Glucagon release was not affected. Beta-cells from mice rendered diabetic on a high-fat diet exhibited a 3.5-fold increase in light-induced Ca²⁺ influx compared with mice on a control diet. Furthermore, light enhanced insulin release also at high glucose in these mice, suggesting that high-fat feeding leads to a compensatory potentiation of the Ca²⁺ response in β-cells.

The results demonstrate the usefulness and versatility of optogenetics for studying mechanisms of perturbed hormone secretion in diabetes with high time-resolution and cell-specificity.     

Potentials of “stem cell-therapy” in pancreatic cancer: An update

In recent times, cell-therapies like T-activated cells, dendritic cells and natural killer cells have shown increasing promise in treating cancers as evidenced by both animal and human studies in the literature. In addition, stem cells are also being considered as potent anti-cancer agents since they act through multi-pronged approaches (chemokines, cytokines, paracrine action). In this review, we have attempted to discuss the inferences of studies that have used different sub-types of stem cells namely mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and neural stem cells (NSCs) in in-vitro/in-vivo mice and/or human studies as a treatment modality for pancreatic cancer. Pancreatic cancers are diagnosed in late/metastatic stages hence limiting its progress to partial/disease-free status. Recent literature supports evidences of stem cell therapy in pancreatic cancer with promising results; yet their impact remains inconclusive due to limited studies in human subjects.With reference to the treatment options for pancreatic cancer, the most studied sub-type of stem cells was HSCs as evident from the available clinical trials. The suggested mechanism of the HSC-transplantation is presumably via the graft-versus-tumor effect that elicits an anti-tumor immune response activated by the T-cell repertoires. On the other hand, the property of MSCs like tropism, migration to tumor site and activation of host immune cells by its secretome, appear to be able to regulate pancreatic tumor microenvironment. Further, drug delivery potential could be mediated via engineered MSCs to enhance the bioavailability of drug/prodrug at tumor site. Conclusively, stem cells have shown great potentials as next-generation therapeutic options.