Prostate cancer proteomics: Current trends and future perspectives for biomarker discovery.

The clinical and fundamental research in prostate cancer - the most common urological cancer in men - is currently entering the proteomic and genomic era. The focus has switched from one single marker (PSA) to panels of biomarkers (including proteins involved in ribosomal function and heat shock proteins). Novel genetic markers (such as Transmembrane protease serine 2 (TMPRSS2)-ERG fusion gene mRNA) or prostate cancer gene 3 (PCA3) had already entered the clinical practice, raising the question whether subsequent protein changes impact the evolution of the disease and the response to treatment. Proteomic technologies such as MALDI-MS, SELDI-MS, i-TRAQ allow a qualitative/quantitative analysis of the proteome variations, in both serum and tumor tissue. A new trend in prostate cancer research is proteomic analysis of prostasomes (prostate-specific exosomes), for the discovery of new biomarkers. This paper provides an update of novel clinical tests used in research and clinical diagnostic, as well as of potential tissue or fluid biomarkers provided by extensive proteomic research data.

Interstitial Outburst of Angiogenic Factors During Skeletal Muscle Regeneration After Acute Mechanical Trauma.

Angiogenesis is a key event during tissue regeneration, but the intimate mechanisms controlling this process are still largely unclear. Therefore, the cellular and molecular interplay along normal tissue regeneration should be carefully unveiled. To this matter, we investigated by xMAP assay the dynamics of some angiogenic factors known to be involved in tissue repair, such as follistatin (FST), Placental Growth Factor-2 (PLGF-2), epidermal growth factor (EGF), betacellulin (BTC), and amphiregulin (AREG) using an animal model that mimics acute muscle contusion injuries. In situ immunofluorescence was used for the evaluation and tissue distribution of their cellular sources. Tissue levels of explored factors increased significantly during degeneration and inflammatory stage of regeneration, peaking first week postinjury. However, except for PLGF-2 and EGF, their levels remained significantly elevated after the inflammatory process started to fade. Serum levels were significantly increased only after 24 h for AREG and EGF. Though, for all factors except FST, the levels in injured samples did not correlate with serum or contralateral tissue levels, excluding the systemic influence. We found significant correlations between the levels of EGF and AREG, BTC, FST and FST and AREG in injured samples. Interstitial cells expressing these factors were highlighted by in situ immunolabeling and their number correlated with measured levels dynamics. Our study provides evidence of a dynamic level variation along the regeneration process and a potential interplay between selected angiogenic factors. They are synthesized, at least partially, by cell populations residing in skeletal muscle interstitium during regeneration after acute muscle trauma.

Potential serum biomarkers for glioblastoma diagnostic assessed by proteomic approaches.

BACKGROUND: The rapid progress of proteomics over the past years has allowed the discovery of a large number of potential biomarker candidates to improve early tumor diagnosis and therapeutic response, thus being further integrated into clinical environment. High grade gliomas represent one of the most aggressive and treatment-resistant types of human brain cancer, with approximately 9-12 months median survival rate for patients with grade IV glioma (glioblastoma). Using state-of-the-art proteomics technologies, we have investigated the proteome profile for glioblastoma patients in order to identify a novel protein biomarker panel that could discriminate glioblastoma patients from controls and increase diagnostic accuracy. RESULTS: In this study, SELDI-ToF MS technology was used to screen potential protein patterns in glioblastoma patients serum; furthermore, LC-MS/MS technology was applied to identify the candidate biomarkers peaks. Through these proteomic approaches, three proteins S100A8, S100A9 and CXCL4 were selected as putative biomarkers and confirmed by ELISA. Next step was to validate the above mentioned molecules as biomarkers through identification of protein expression by Western blot in tumoral versus peritumoral tissue. CONCLUSIONS: Proteomic technologies have been used to investigate the protein profile of glioblastoma patients and established several potential diagnostic biomarkers. While it is unlikely for a single biomarker to be highly effective for glioblastoma diagnostic, our data proposed an alternative and efficient approach by using a novel combination of multiple biomarkers.

Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics.

Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.

Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy - a case report.

Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb®) in combination with continuous veno-venous haemofiltration was associated with a decrease in TNFα, IL-1ß and IFNγ and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb® on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb® and to evaluate the overall outcome.

Signal transduction molecule patterns indicating potential glioblastoma therapy approaches.

PURPOSE: The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients' glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatidylinositol-3'-kinase (PI3K) inhibitor. PATIENTS AND METHODS: xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. RESULTS: PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. CONCLUSION: The PI3K pathway might be a prime target for glioblastoma treatment.

Anti-cancer Therapies in High Grade Gliomas.

High grade gliomas represent one of the most aggressive and treatment-resistant types of human cancer, with only 1-2 years median survival rate for patients with grade IV glioma. The treatment of glioblastoma is a considerable therapeutic challenge; combination therapy targeting multiple pathways is becoming a fast growing area of research. This review offers an up-to-date perspective of the literature about current molecular therapy targets in high grade glioma, that include angiogenic signals, tyrosine kinase receptors, nodal signaling proteins and cancer stem cells related approaches. Simultaneous identification of proteomic signatures could provide biomarker panels for diagnostic and personalized treatment of different subsets of glioblastoma. Personalized medicine is starting to gain importance in clinical care, already having recorded a series of successes in several types of cancer; nonetheless, in brain tumors it is still at an early stage.

Cytokine patterns in brain tumour progression.

Inflammation represents the immune system response to external or internal aggressors such as injury or infection in certain tissues. The body's response to cancer has many parallels with inflammation and repair; the inflammatory cells and cytokines present in tumours are more likely to contribute to tumour growth, progression, and immunosuppression, rather than in building an effective antitumour defence. Using new proteomic technology, we have investigated serum profile of pro- (IL-1ß , IL-6, IL-8, IL-12, GM-CSF, and TNF-α ) and anti-inflammatory cytokines (IL-4, IL-10), along with angiogenic factors (VEGF, bFGF) in order to assess tumoural aggressiveness. Our results indicate significant dysregulation in serum levels of cytokines and angiogenic factors, with over threefold upregulation of IL-6, IL-1ß , TNF-α , and IL-10 and up to twofold upregulation of VEGF, FGF-2, IL-8, IL-2, and GM-CSF. These molecules are involved in tumour progression and aggressiveness, and are also involved in a generation of disease associated pain.

Advances in pancreatic cancer detection.

Pancreatic cancer represents a major challenge for research studies and clinical management. No specific tumor marker for the diagnosis of pancreatic cancer exists. Therefore, extensive genomic, transcriptomic, and proteomic studies are being developed to identify candidate markers for use in high-throughput systems capable of large cohort screening. Understandably, the complex pathophysiology of pancreatic cancer requires sensitive and specific biomarkers that can improve both early diagnosis and therapeutic monitoring. The lack of a single diagnostic marker makes it likely that only a panel of biomarkers is capable of providing the appropriate combination of high sensitivity and specificity. Biomarker discovery using novel technology can improve prognostic upgrading and pinpoint new molecular targets for innovative therapy.

Key signaling molecules in pituitary tumors.

In pituitary tumorigenesis there is cross-talk between fine deregulation of intracellular pathways and complex microenvironmental factors, processes that can be modulated at various levels. The signaling pathways of growth, angiogenic factors and hormones are intricate; therefore, alterations induced upon node-molecules can lead to aberrant proliferation. The demonstrated overactivity of AKT and MAPK pathways qualifies them as valuable targets for inhibition mediated by somatostatin analogues. An increasing body of evidence suggests clinically significant implications of PTTG1 in correlation with aggressive phenotypes or survival rate, thus PTTG1 is an interesting candidate biomarker for malignancy, tumor staging and subsequent therapeutic interventions. Future work should focus on understanding the molecular mechanisms that control pituitary tumor transformation, where intracellular signaling molecules will constitute not only diagnostic/prognostic markers but also novel therapeutic targets.

Caveolin-1 overexpression correlates with tumour progression markers in pancreatic ductal adenocarcinoma.

The assessment of caveolin-1 (Cav-1) as a marker of tumor aggressiveness in pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the expression of Cav-1 in 34 human PDAC tissue samples and the associated peritumoral tissues by immunohistochemistry and western blot. Additionally, we correlated Cav-1 expression with other tissue (Ki-67, p53) and serum (CA 19-9) tumor markers. In the tumor-derived tissue, both tumor cells and blood vessels expressed Cav-1. In contrast, in peritumoral tissue, Cav-1 expression was confined mainly to blood vessels and was only occasionally expressed in ductal or parenchymal cells. Western blot analysis confirmed the overexpression of Cav-1 in pancreatic tumors compared with peritumoral tissue. Cav-1 expression in tumor tissues was correlated with both the Ki-67 LI (r = 0.95, P < 0.0001) and p53 expression (chi2 = 9.91, P < 0.005). Overexpression of Cav-1 was associated with tumor size, grade and stage and Cav-1 expression in tumors was correlated with an increased serum level of CA 19-9 (r = 0.795, P < 0.001). Based on the results of this study, the inclusion of Cav-1 in a putative panel of biomarkers predicting pancreatic cancer aggressiveness is warranted.

Biomarkers in the diagnosis and early detection of pancreatic cancer.

BACKGROUND: Pancreatic cancer, owing to its raising incidence and aggressiveness, is a major challenge, both for research and for clinical management. As pancreatic cancer has a complex pathophysiology, in addition to improving the methods of early diagnosis, sensitive and specific biomarkers are a prerequisite. OBJECTIVE: As there is no specific tumor marker for pancreatic cancer diagnosis, extensive genomics/transcriptomics and proteomics studies have been developed with the aim of finding candidate markers and contributing to high-throughput systems for large cohort screening. METHODS: A literature review was done to study these biomarkers in relation to diagnosis, prognosis and therapy targets in pancreatic cancer. RESULTS/CONCLUSION: For early diagnosis improvement, only a panel of soluble biomarkers could provide the appropriate combination between high sensitivity and specificity. Prognostic upgrading would benefit from biomarker discovery and validation performed on tumor tissue. New technology could delineate molecular targets for innovative therapy in pancreatic cancer.

Caveolin-1: a marker for pancreatic cancer diagnosis.

Pancreatic ductal adenocarcinoma is the fourth most common cause of cancer death, but the prognosis and management of patients have remained unchanged despite the progress in understanding the molecular basis of this disease. There is no specific/sensitive tumor marker for pancreatic cancer, thus the battle of searching for new and validated tumor markers has become a hot topic. Among various new markers, caveolin-1 - with its dual function in cancer - stands apart due to its relation to the development and progression stage of cancer. Caveolin-1 has been considered an independent unfavorable prognostic factor, its level being elevated and related to tumor size and histological grade. Our experimental data confirmed the link between tissue caveolin-1 and classical proliferation markers in pancreatic ductal adenocarcinoma, and its overexpression was validated by western blot and correlated with tumor aggressiveness. Although the studies on caveolin-1 and pancreatic cancer are only preliminary and reveal conflicting data, this review aims to signal that caveolin-1, as a versatile signaling molecule, may represent a valuable marker in this type of cancer. For caveolin-1 we can foresee two future directions of development: validation it as a biomarker and/or as an anticancer therapy target.