Glycan alterations of serum proteins as tumour markers. Prostate-specific antigen in prostate cancer and acute-phase proteins in pancreatic cancer

Els pacients amb càncer presenten una taxa de supervivència superior si es diagnostiquen a estadis inicials, per la qual cosa és indispensable disposar de marcadors tumorals adequats. Glicoformes de proteïnes específiques es podrian utilizar com marcadors tumorals. S’han investigat les subformes i glicosilació de l’Antígen Prostàtic Específic (PSA) per millorar la seva capacitat de diagnosis de pacients amb càncer de pròstata vs aquells amb hiperplàsia benigna prostàtica. També s’han avaluat glicoproteïnes sèriques amb alteracions glucídiques en pacients de càncer de pàncrees, comparat amb pacients amb pancreatitis crònica i controls. S’ha observat una disminució de la fucosilació core i sialilació del PSA en càncer de pròstata i un augment de la fucosilació core i Sialyl-Lewis X en algunes Proteïnes de fase Aguda en càncer de pàncrees. Aquest canvis s’haurien d’avaluar en un cohort de pacients més gran per determinar el seu paper en el cribratge, diagnòstic o monitorització dels cancers estudiats.

Pancreatic cancer: medical management (novel chemotherapeutics)

Pancreatic adenocarcinoma is the fourth leading cause of cancer death and has an extremely poor prognosis: The 5-year survival probability is less than 5% for all stages. The only chance for cure or longer survival is surgical resection; however, only 10% to 20% of patients have resectable disease. Although surgical techniques have improved, most who undergo complete resection experience a recurrence. Adjuvant systemic therapy reduces the recurrence rate and improves outcomes. There is a potential role for radiation therapy as part of treatment for locally advanced disease, although its use in both the adjuvant and neoadjuvant settings remains controversial. Palliative systemic treatment is the only option for patients with metastatic disease. To date, however, only the gemcitabine plus erlotinib combination, and recently the FOLFIRINOX regimen, have been associated with relatively small but statistically significant improvements in OS when compared directly with gemcitabine alone. Although several meta-analyses have suggested a benefit associated with combination chemotherapy, whether this benefit is clinically meaningful remains unclear, particularly in light of the enhanced toxicity associated with combination regimens. There is growing evidence that the exceptionally poor prognosis in PC is caused by the tumor's characteristic abundant desmoplastic stroma that plays a critical role in tumor cell growth, invasion, metastasis, and chemoresistance. Carefully designed clinical trials that include translational analysis will provide a better understanding of the tumor biology and its relation to the host stromal cells. Future directions will involve testing of new targeted agents, understanding the pharmacodynamics of our current targeted agents, searching for predictive and prognostic biomarkers, and exploring the efficacy of different combinations strategies.

Latitude variation in pancreatic cancer mortality in Australia

Objectives: Ecological studies support the hypothesis that there is an association between vitamin D and pancreatic cancer (PaCa) mortality, but observational studies are somewhat conflicting. We sought to contribute further data to this issue by analyzing the differences in PaCa mortality across the eastern states of Australia and investigating if there is a role of vitamin D-effective ultraviolet radiation (DUVR), which is related to latitude. ---------- Methods: Mortality data from 1968 to 2005 were sourced from the Australian General Record of Incidence and Mortality books. Negative binomial models were fitted to calculate the association between state and PaCa mortality. Clear sky monthly DUVR in each capital city was also modeled. ---------- Results: Mortality from PaCa was 10% higher in southern states than in Queensland, with those in Victoria recording the highest mortality risk (relative risk, 1.13; 95% confidence interval, 1.09-1.17). We found a highly significant association between DUVR and PaCa mortality, with an estimated 1.5% decrease in the risk per 10-kJ/m2 increase in yearly DUVR. ---------- Conclusions: These data show an association between latitude, DUVR, and PaCa mortality. Although this study cannot be used to infer causality, it supports the need for further investigations of a possible role of vitamin D in PaCa etiology.

Prostate cancer biomarkers and the emerging proteomic techniques used in biomarker research

Prostate cancer (CaP) is the second leading cause of cancer-related deaths in North American males and the most common newly diagnosed cancer in men world wide. Biomarkers are widely used for both early detection and prognostic tests for cancer. The current, commonly used biomarker for CaP is serum prostate specific antigen (PSA). However, the specificity of this biomarker is low as its serum level is not only increased in CaP but also in various other diseases, with age and even body mass index. Human body fluids provide an excellent resource for the discovery of biomarkers, with the advantage over tissue/biopsy samples of their ease of access, due to the less invasive nature of collection. However, their analysis presents challenges in terms of variability and validation. Blood and urine are two human body fluids commonly used for CaP research, but their proteomic analyses are limited both by the large dynamic range of protein abundance making detection of low abundance proteins difficult and in the case of urine, by the high salt concentration. To overcome these challenges, different techniques for removal of high abundance proteins and enrichment of low abundance proteins are used. Their applications and limitations are discussed in this review. A number of innovative proteomic techniques have improved detection of biomarkers. They include two dimensional differential gel electrophoresis (2D-DIGE), quantitative mass spectrometry (MS) and functional proteomic studies, i.e., investigating the association of post translational modifications (PTMs) such as phosphorylation, glycosylation and protein degradation. The recent development of quantitative MS techniques such as stable isotope labeling with amino acids in cell culture (SILAC), isobaric tags for relative and absolute quantitation (iTRAQ) and multiple reaction monitoring (MRM) have allowed proteomic researchers to quantitatively compare data from different samples. 2D-DIGE has greatly improved the statistical power of classical 2D gel analysis by introducing an internal control. This chapter aims to review novel CaP biomarkers as well as to discuss current trends in biomarker research from two angles: the source of biomarkers (particularly human body fluids such as blood and urine), and emerging proteomic approaches for biomarker research.

Pancreatic cancer – a patient and his doctor balance hope and truth [Book Review]

This book comprises 11 chapters, alternating between two authors (a patient with metastatic pancreatic cancer and an oncologist)...

Beyond survivorship? A discursive analysis of how people with pancreatic cancer negotiate identity transitions in their health

We explored how people negotiate, and respond to, identity transitions following a diagnosis of pancreatic cancer. Interviews with 19 people with pancreatic cancer were analysed using thematic discourse analysis. While discursively negotiating two transitions, “moving from healthy to ill” and “moving from active treatment to end-of-life care”, participants positioned themselves as “in control”, “optimistic” and managing their health and illness. In the absence of other discourses or “models” of life post-cancer, many people draw on the promise of survival. Moving away from “survivorship” may assist people with advanced cancer to make sense of their lives in a short timeframe.

Occupational determinants of pancreatic cancer

Objective and background. Tobacco smoking, pancreatitis and diabetes mellitus are the only known causes of pancreatic cancer, leaving ample room for yet unidentified determinants. This is an empirical study on a Finnish data on occupational exposures and pancreatic cancer risk, and a non-Bayesian and a hierarchical Bayesian meta-analysis of data on occupational factors and pancreatic cancer. Methods. The case-control study analyzed 595 incident cases of pancreatic cancer and 1,622 controls of stomach, colon, and rectum cancer, diagnosed 1984-1987 and known to be dead by 1990 in Finland. The next-of-kin responded to a mail questionnaire on job and medical histories and lifestyles. Meta-analysis of occupational risk factors of pancreatic cancer started off with 1,903 identified studies. The analyses were based on different subsets of that database. Five epidemiologists examined the reports and extracted the pertinent data using a standardized extraction form that covered 20 study descriptors and the relevant relative risk estimates. Random effects meta-analyses were applied for 23 chemical agents. In addition, hierarchical Bayesian models for meta-analysis were applied to the occupational data of 27 job titles using job exposure matrix as a link matrix and estimating the relative risks of pancreatic cancer associated with nine occupational agents. Results. In the case-control study, logistic regressions revealed excess risks of pancreatic cancer associated with occupational exposures to ionizing radiation, nonchlorinated solvents, and pesticides. Chlorinated hydrocarbon solvents and related compounds, used mainly in metal degreasing and dry cleaning, are emerging as likely risk factors of pancreatic cancer in the non-Bayesian and the hierarchical Bayesian meta-analysis. Consistent excess risk was found for insecticides, and a high excess for nickel and nickel compounds in the random effects meta-analysis but not in the hierarchical Bayesian meta-analysis. Conclusions. In this study occupational exposure to chlorinated hydrocarbon solvents and related compounds and insecticides increase risk of pancreatic cancer. Hierarchical Bayesian meta-analysis is applicable when studies addressing the agent(s) under study are lacking or very few, but several studies address job titles with potential exposure to these agents. A job-exposure matrix or a formal expert assessment system is necessary in this situation.

Prognostic tumour markers in pancreatic cancer

Background. Pancreatic cancer is one of the major causes of cancer death in the industrialised world. The overall survival of patients with ductal pancreatic adenocarcinoma is poor: 5-year survival is only 0.2 to 4%. Tumour stage and histological grade are used as prognostic markers in pancreatic cancer. However, there are differences in survival within stages and histological grades. New, additional and more accurate prognostic tools are needed. Aims. The purpose of this study was to investigate whether the tissue expression of potential and promising tumour markers p27, tenascin C, syndecan-1, COX-2 and MMP-2 are associated with clinicopathological parameters in pancreatic cancer. The expression of p27, tenascin C and syndecan-1 was also evaluated in acute and chronic pancreatitis. The main purpose in the study was to find new prognostic markers for pancreatic adenocarcinoma. Patients. The study included 147 patients with histologically verified pancreatic adenocarcinoma treated at Helsinki University Central Hospital from 1974 to1998. Methods. The expression of tumour marker antigens was demonstrated by immunohistochemistry using monoclonal antibodies against p27, syndecan-1, tenascin C, COX-2 and MMP-2. The results were compared with clinicopathological variables, i.e. age, sex, TNM stage and histological grade. Survival analyses were performed with univariate Kaplan-Meier life-tables and the log-rank test, while multivariate analyses were performed using Cox regression. Results. Pancreatic adenocarcinomas expressed p27, syndecan-1, tenascin C, COX-2 and MMP-2 in 30, 94, 92, 36 and 50% of the samples, respectively. Loss of p27 expression was associated with poor prognosis in stage I and II pancreatic cancer. Stromal syndecan-1 expression was an independent prognostic marker in pancreatic cancer, whereas epithelial syndecan-1 expression predicted better prognosis only in stage I and II disease. Tenascin C expression did not correlate with survival but was associated with differentiation. COX-2 expression was associated with poor outcome and was an independent prognostic factor. Epithelial MMP-2 correlated with poor prognosis in pancreatic cancer. Conclusion: p27 and epithelial syndecan-1 are prognostic markers in early (stage I and II) pancreatic cancer. Stromal syndecan-1, COX-2 and epithelial MMP-2 are prognostic factors in ductal pancreatic adenocarcinoma.

RAD51 as a potential biomarker and therapeutic target for pancreatic cancer

Chemotherapy is a very important therapeutic strategy for cancer treatment. The failure of conventional and molecularly targeted chemotherapeutic regimes for the treatment of pancreatic cancer highlights a desperate need for novel therapeutic interventions. Chemotherapy often fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Overexpression of RAD51 protein, a key player in DNA repair/recombination has been observed in many cancer cells and its hyperexpression is implicated in drug resistance. Recent studies suggest that RAD51 overexpression contributes to the development, progression and drug resistance of pancreatic cancer cells. Here we provide a brief overview of the available pieces of evidence in support of the role of RAD51 in pancreatic tumorigenesis and drug resistance, and hypothesize that RAD51 could serve as a potential biomarker for diagnosis of pancreatic cancer. We discuss the possible involvement of RAD51 in the drug resistance associated with epithelial to mesenchymal transition and with cancer stem cells. Finally, we speculate that targeting RAD51 in pancreatic cancer cells may be a novel approach for the treatment of pancreatic cancer. (C) 2011 Elsevier B.V. All rights reserved.

Differential activity of GSK-3 isoforms regulates NF-kappa B and TRAIL- or TNF alpha induced apoptosis in pancreatic cancer cells

While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3 alpha or GSK-3 beta. In contrast, depletion of GSK-3 beta, but not GSK-3 alpha, sensitized PDA cell lines to TNF alpha-induced cell death. Further experiments demonstrated that TNF alpha-stimulated I kappa B alpha phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3 beta-deficient MEFs. Nonetheless, inhibition of GSK-3 beta function in MEFs or PDA cell lines impaired the expression of the NF-kappa B target genes Bcl-xL and cIAP2, but not I kappa B alpha. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3 beta targeted to the nucleus but not GSK-3 beta targeted to the cytoplasm, suggesting that GSK-3 beta regulates NF-kappa B function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3 beta overexpression and nuclear localization contribute to TNF alpha and TRAIL resistance via anti-apoptotic NF-kappa B genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.

Infiltration of myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis in many types of cancer. The polypeptide chemokine PK2 (Bv8, PROK2) has been shown to regulate myeloid cell mobilization from the bone marrow, leading to activation of the angiogenic process, as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 were shown to display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. In this study we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the context of glioblastoma and pancreatic cancer xenograft tumor models. For the highly vascularized glioblastoma, PKRA7 was associated with decreased blood vessel density and increased necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 appears to be mediated by the blockage of myeloid cell migration/infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of certain pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both types of tumor. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by two distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.

The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer.

BACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.