Tumor metastasis is challenged by its resistance to microenvironmental stress infringed during escape from the primary tumor and the colonization of a foreign secondary tissue. Because of its great metastatic potential and its strong resistance to anticancer drugs, pancreatic cancer is regarded as a paradigm of the adaptation of cancer cells to microenvironmental stress. Thus, to understand how pancreatic cancer cells adapt to the different endogenous and therapy-related stresses is crucial for understanding their etiology and for the development of new efficient anticancer strategies. This review summarizes the multiple functions accomplished by one major factor of pancreatic cancer cell stress response, the stress protein p8.

Carla E. Cano

Juan L. Iovanna

Stress Proteins and Pancreatic Cancer Metastasis

Epithelial to mesenchymal transition (EMT) is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/aggressiveness, and the drug resistance of pancreatic cancer cells.

Carla Cano

Yoshiharu Motoo

Epithelial-to-Mesenchymal Transition in Pancreatic Adenocarcinoma

Pancreatic cancer (PC) is one of the most difficult illnesses to treat, since the 5-year survival rate is lower than 5% in patients and no substantial advances in its treatment have been achieved in the last 20 years. Since cancer deregulation and progression are associated with changes in at least one biochemical pathway, the knowledge of the structure of the proteins involved in such routes seems to be crucial in order to understand how this cancer progresses and, more importantly, to design more efficient and rationally designed drugs. In this review, we describe the fold and structures of proteins involved in different signaling pathways that intervene during PC development and progression. In particular, we will focus on the most frequently mutated, or alternatively differently expressed, proteins in PC. The current knowledge suggests that most of the proteins carry out their function by interacting with others via specific domains and through key residues at the recognition interfaces; these amino acids are mutated in patients developing PC. Furthermore, phosphorylation seems to be a crucial regulation step along several signaling pathways. Finally, we show not only that well-folded proteins in several signaling pathways are critical in the development of PC, but also that natively unfolded “hub” proteins, able to interact with DNA or proteins, are also important in such cancer progression.

Jerónimo Bravo

José L. Neira

Folded and Unfolded Conformations of Proteins Involved in Pancreatic Cancer: a Layman's Guide

Pancreatic cancer is one of the worst, as almost 100&#x25; of patients will die within 5 years after diagnosis. The tumors are characterized by an early, invasive, and metastatic phenotype, and extreme resistance to all known anticancer therapies. Therefore, there is an urgent need to develop new investigative strategies in order to identify new molecular targets and, possibly, new drugs to fight this disease efficiently. Whereas it has been known for more than 3 decades now, ubiquitylation is a post-translational modification of protein that only recently emerged as a major regulator of many biological functions, dependent and independent on the proteasome, whose failure is involved in many human diseases, including cancer. Indeed, despite its role in promoting protein degradation through the proteasome, ubiquitylation is now known to regulate diverse cellular processes, such as membrane protein endocytosis and intracellular trafficking, assembly of protein complexes, gene transcription, and activation or inactivation of enzymes. Taking into account that ubiquitylation machinery is a three-step process involving hundreds of proteins, which is countered by numerous ubiquitin hydrolases, and that the function of ubiquitylation relies on the recognition of the ubiquitin signals by hundreds of proteins containing a ubiquitin binding domain (including the proteasome), the number of possible therapeutic targets is exceptionally vast and will need to be explored carefully for each disease. In the case of pancreatic cancer, the study and the identification of specific alteration(s) in protein ubiquitylation may help to explain its severity and may furnish more specific targets for more efficient therapies.

Thomas Bonacci

Julie Roignot

Philippe Soubeyran

Protein Ubiquitylation in Pancreatic Cancer

Pancreatic cancer (PC) is the fourth leading cause of cancer death, with a median survival of 6 months and a dismal 5-year survival rate of 35%, a figure which has remained relatively unchanged over the past 25 years. PC is one of the most difficult diseases to treat due to late initial diagnosis and to resistance to the usual treatments. The presence of occult or clinical metastases at the time of diagnosis, together with the lack of effective chemotherapies, contributes to the high mortality in patients with PC. Its lethal nature stems from its propensity to disseminate rapidly to the lymphatic system and distant organs. Yet, understanding and stopping metastasis may prove to be one of the great potential strategies of treating PC.  There is a dire need for the design of new and targeted therapeutic strategies that can overcome the drug resistance and improve the clinical outcome for patients diagnosed with the illness. The knowledge of the molecular aspects of PC is very important, and it is likely to be helpful in the design of newer drugs and the molecular selection of existing agents for targeted therapy. The inhibition of signal pathways can be carried out not only by small molecules, able to bind to selected regions of the target protein, but also by using large molecules as antibodies. The pathway to successful new therapies has been inhibited because of the rapidity with which agents tend to move into randomized, controlled trials without the extensive early testing necessary to optimize treatment regimens. However, lessons have been learned and our collective research effort has generated a substantial platform of knowledge from which further work will spring. The bioavailability of compounds such as antisense oligonucleotides and siRNAs in humans remains a big hurdle, which will require further improvement of gene-delivery strategies. Finally, the long-term goal of the therapy individualization for patients is possible if factors that predict treatment response, such as biological markers, could be determined accurately. These approaches are likely to comprise a mixture of targeted agents in combination with conventional chemotherapy and radiotherapy. For a clinically significant effect to be achieved, treatment strategies should either be in the form of (1) a horizontal approach, in which several oncogenic pathways (as those described in this series of reviews) are inhibited; or (2) a vertical approach, whereby multiple levels of a major pathway are targeted. Combination therapies, together with improved diagnostic tools and predictive markers, are ultimately desired in order to improve the bleak outlook for patients diagnosed with PC.

Juan Iovanna

Jos&#233; Luis Neira

Pancreatic Cancer: Molecular, Biochemical, Chemopreventive, and Therapeutic Aspects

Pancreatic cancer is a devastating disease with the worst mortality rate and an overall 5-year survival rate lower than 5%. In the U.S., this disease is the fourth leading cause of death and represents 6% of all cancer-related deaths. Gemcitabine, the current standard first-line treatment, offers marginal benefits to patients in terms of symptom control and prolongation of life. Since 1996, about 20 randomized phase III trials have been performed to improve the efficacy of gemcitabine, with little success regarding a significant improvement in survival outcomes. The need for novel therapeutic strategies, such as target therapy, is obvious. Monoclonal antibodies have finally come of age as therapeutics and several molecules are now approved for cancer therapies. This review aims to give a general view on the clinical results obtained so far by antibodies for the treatment of pancreatic cancer and describes the most promising avenues toward a significant improvement in the treatment of this frustrating disease.

Patrick Chames

Brigitte Kerfelec

Daniel Baty

Therapeutic Antibodies for the Treatment of Pancreatic Cancer

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