Current Pharmaceutical Design - Volume 18, Issue 17, 2012

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Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.

Recent studies have demonstrated that the interaction between the cancer and the stroma, play a key role in the development of pancreatic cancer. The desmoplasia, which consists of fibroblasts, pancreatic stellate cells, lymphatic and vascular endothelial cells, immune cells, pathologic increased nerves, and the extracellular matrix (ECM), creates a complex tumor microenvironment that promotes pancreatic cancer development, invasion, metastasis, and resistance to chemotherapy. Thus, the potential approach for targeting the components of this desmoplastic reaction or the pancreatic tumor microenvironment might represent a novel therapeutic approach to advanced pancreatic carcinoma. Novel therapies that target on the pancreatic tumor microenvironment should become one of the more effective treatments for pancreatic cancer.

Increasing evidence has shown that cytokines have a role in tumor biology. The role of chemokines in tumor biology is important because these peptides may influence tumor growth, invasion, angiogenesis, and metastasis. In this review, we demonstrated the role of cytokines (Interleukin-1α, hepatocyte growth factor, Interleukin-8, stromal cell-derived factor-1 and CXC-chemokines/CXCR2 biological axis) in pancreatic cancer angiogenesis, especially from the standpoint of the interaction between tumor and its microenvironments. The cytokines are intimately related with cancer angiogenesis. Blocking these cytokines could attenuate pancreatic cancer associated angiogenesis and further considered as a novel anti-angiogenic target in pancreatic cancer.

Tumor angiogenesis play a significant role in genesis, development and metastasis of pancreatic cancer though the process is different from angiogenesis in normal tissues. VEGF, one of the most important angiogenesis factors, is modulated by inflammation factors as well as transcriptional factors, such as members of Sp/KLF family. Recent research showed that VEGF related inflammation factors and Sp/KLF family members form a complex network structure, which causes genesis and development of tumor. Conceivably, fully understanding the mechanism linking VEGF related inflammation factors and Sp/KLF family members would promote the concept of tumor angiogenesis. Furthermore, it could also help to design effective strategies to target the key components of the network and control the development and progression of tumor.

Over the last decade it has been established that cancer-associated inflammation affects many aspects of malignancy and in particular endorses tumor cell survival, proliferation and distant spread. Chemokines and their receptors are major players of the cancerrelated inflammation. Our understanding of the chemokine role in tumor biology now ranges from their ability to recruit blood leukocytes within tumors, to direct effects on cancer cell survival, metastatization and regulation of angiogenesis. Chemokines and their receptors are expressed in human pancreatic adenocarcinoma and are involved in its malignant behavior. Notably, the receptor CX3CR1 favors tumor perineural tropism which is typical of this neoplasm and is associated with early recurrence after surgery and with poor patient prognosis.

Pancreatic cancer (PC) is a leading cause of cancer related deaths in United States. The lack of early symptoms results in latestage detection and a high mortality rate. Currently, the only potentially curative approach for PC is surgical resection, which is often unsuccessful because the invasive and metastatic nature of the tumor masses makes their complete removal difficult. Consequently, patients suffer relapses from remaining cancer stem cells or drug resistance that eventually lead to death. To improve the survival rate, the early detection of PC is critical. Current biomarker research in PC indicates that a serum carbohydrate antigen, CA 19-9, is the only available biomarker with approximately 90% specificity to PC. However, the efficacy of CA 19-9 for assessing prognosis and monitoring patients with PC remains contentious. Thus, advances in technology and the detection of new biomarkers with high specificity to PC are needed to reduce the mortality rate of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating disease, which is characterized by invasiveness and dissemination to the lymphatic system and distant organs. In the absence of effective screening methods considerable efforts have thus been made to identify better systemic treatments than gemcitabine, the standard of care for advanced PDAC for well over a decade. However, until now only erlotinib, an epidermal growth-factor receptor tyrosine kinase inhibitor, has demonstrated a modest survival benefit in combination with gemcitabine in a phase III clinical trial. More recently, detailed global genomic analyses have provided a snapshot of the landscape of tumor genomes by showing that they contain four high frequency mutated genes and many low frequency mutated genes that correspond to 12 core signaling pathways. Strategies to target these frequently altered genes and their pathways, or low frequency mutated genes corresponding to the “personalized genome”, offer novel therapeutic strategies. In the near future, the complete sequencing of the coding genome, together with the dramatically reduced costs of whole genome sequencing, will provide new opportunities to treat PDAC.

Pancreatic cancer is characterized by its intrinsic resistance to cytotoxic agents. But the underlying molecular mechanism is unclear. Studies demonstrate that angiogenesis, presence of highly resistant cancer stem cells (CSCs), dysregulation of cell cycle and apoptosis are main aspects of mechanisms of pancreatic cancer chemoresistance. Interestingly, recent investigations of Wnt/β-catenin signaling suggest roles for the signaling in these four aspects and the pathogenesis of pancreatic cancer. Conceivably, the dysregulation of Wnt/β-catenin signaling pathway is involved in pancreatic cancer chemoresistance. Though researchers have proven it in some other cancer types, however, there is no direct evidence for this reasoning in pancreatic cancer. Designing effective experiment setups to define the function and mechanism of Wnt/β-catenin signaling in pancreatic cancer chemoresistance and subsequently targeting the signaling to improve the sensitivity of chemotherapy in pancreatic cancer require a full understanding of the molecular mechanisms of Wnt/β-catenin signaling pathway in angiogenesis, maintaining of highly resistant CSCs, regulation of cell cycle and apoptosis in pancreatic cancer.

The prognosis of pancreatic cancer (PC) patients is very poor with a five-year survival of less than 5%. One of the major challenges in developing new therapies for PC is the lack of expression of specific markers by pancreatic tumor cells. Mucins are heavily Oglycosylated proteins characterized by the presence of short stretches of amino acid sequences repeated several times in tandem. The expression of several mucins including MUC1, MUC4, MUC5AC, and MUC16 is strongly upregulated in PC. Recent studies have also demonstrated a link between the aberrant expression and differential overexpression of mucin glycoproteins to the initiation, progression, and poor prognosis of the disease. These studies have led to increasing recognition of mucins as potential diagnostic markers and therapeutic targets in PC. In this focused review we present an overview of the therapies targeting mucins in PC, including immunotherapy (i.e. vaccines, antibodies, and radioimmunoconjugates), gene therapy, and other novel therapeutic strategies.

Polycystic Ovary Syndrome (PCOS) is one of the common endocrine diseases that affects women in their reproductive age. PCOS has diverse clinical implications that include reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, cardiovascular diseases) and psychological features (increased anxiety, depression and worsened quality of life). The exact patho-physiology of PCOS is complex and remains largely unclear. The prevalence of PCOS is estimated at 4-18%, depending on diverse factors discussed ahead. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and body weight. During the last decades, obesity and excess weight are major chronic diseases all around the word. Obesity increases some features of PCOS such as hyperandrogenism, hirsutism, infertility and pregnancy complications. Both obesity and insulin resistance increase diabetes mellitus type 2 and cardiovascular diseases. Moreover, obesity impairs insulin resistance and exacerbates reproductive and metabolic features of PCOS. It is well known that obesity is associated with anovulation, pregnancy loss and late pregnancy complications (pre-eclampsia, gestational diabetes). Obesity in PCOS is also linked to failure or delayed response to the various treatments including clomiphene citrate, gonadotropins and laparoscopic ovarian diathermy. It has been reported that, after losing as little as 5 % of initial body weight obese women with PCOS improved spontaneous ovulation rates and spontaneous pregnancy. Therefore, the weight loss prior to conception improves live birth rate in obese women with or without PCOS. The treatment of obesity may include lifestyle therapy (diet and exercise), pharmacological treatment and bariatric surgery. In summary, weight loss is considered the first-line therapy in obese women with PCOS. In the present review, the consequence and treatment of obesity in women with PCOS are discussed.

Protein kinase C (PKC) is a family of serine/threonine kinases involved in the transduction of signals that control different cellular processes, such as cell death and proliferation. This family comprises at least 10 isoforms that regulate apoptosis in an isoformspecific manner. However, controversial data about the role of individual PKC isoforms in apoptosis regulation are frequently reported. The co-existence of several PKC isoforms in a same mammalian cell, the distinct expression profile of PKC isoforms in different cell types, and the different stimulus applied may explain such contradicting results. Therefore major advances in the understanding of the molecular mechanisms that regulate the function of PKC isoforms in apoptosis are still required. Yeast has proved to be a valuable research tool to investigate molecular aspects of apoptosis regulation. Additionally, the conservation in yeast of major functional and molecular properties of mammalian PKC isoforms favours the use of this simpler cell model to uncover relevant aspects of apoptosis regulation by this kinase family. In this review, we cover the current knowledge about the role of different PKC isoforms in apoptosis. Moreover, we discuss the contribution of yeast to unravel several controversial issues about apoptosis regulation by PKC isoforms. The exploitation of yeast cells expressing individual PKC isoforms towards the identification of isoform-specific PKC modulators is also discussed. The studies here summarised highlight that the yeast cell model system can provide valuable insights in the PKC research field.

Multimerization offers unique kinetic and thermodynamic properties to molecules. Multimeric ligands, characterized by multiple similar or different monomeric molecules tethered together, can bind several receptors simultaneously. Multimerization occurs also in nature. This process can be used to develop molecules with high diagnostic and therapeutic value. By altering parameters as linkers` length and flexibility, scaffold and backbones insertion, and ligands-receptors recognition, it is possible to provide high selectivity and binding affinity. The resultant multimeric ligand has a more favorable binding affinity than corresponding monomeric ligands.