At the Translational Workshop on “Mechanisms of Cell Death and Diseases” held at Villa Vigoni, Loveno die Menaggio, Italy, 20 physicians and scientists met to exchange scientific knowledge and recent findings in a clinical context.

In keeping up with the previous workshops on cell death, this year’s meeting was full of discussion fostering numerous scientific collaborations among the participants -  European research groups working on programmed cell death.

Pathways of programmed cell death, including apoptosis and autophagy, play an important role in the pathogenesis of inflammatory and malignant diseases. Whereas increased apoptosis can be observed i.e. in inflammatory diseases, malignant diseases are generally characterized by decreased apoptosis rates. Consequently, understanding of the molecular mechanisms leading to dysregulated cell death is important for the development of novel diagnostic and therapeutic treatment strategies.

One of the key foci of the workshop was the role of the tumor suppressor p53 and the p53 family members p63 and p73 in tumor development as well as in conferring resistance to chemotherapy. Many anticancer agents induce DNA damage as part of their mechanism of tumor cytotoxicity. DNA damage activates p53, which in turn induces the expression of proteins that halt the cell-division cycle to allow for DNA repair. Upon severe DNA damage activation of p53 can also initiate programs of cell death (apoptosis) or permanent growth arrest (senescence). Related proteins p63 and p73 were discussed as being important for normal development and differentiation, but also to be implicated in tumorigenesis and the response to chemo- or radiotherapies.

From clinical as well as scientific investigations dealing with the tumor promoting transcription factor Nuclear factor kB (NFkB) we learned about potential new roles of NFkB activation which, in concert with DNA damaging agents, may be converted into a promoter of apoptotic cell death. These finding are of utmost clinical importance with regard to the development of new therapeutic strategies, because currently rather inhibition of NFkB activity is in the focus of cancer treatment.

In addition to apoptosis, autophagy is another “self eliminating” process being as important but currently much less understood. The workshop allowed for presentation of the most recent molecular findings about the role of autophagy in immune responses. New data suggest that autophagic pathways regulate the differentiation of immune cells which contributes to the protection from cancer development. Representatives of a biomedical company presented reverse peptides designed as very promising candidates to fight inflammatory diseases which play also a role for specific inflammation-mediated tumor entities.

Hot topics of the workshop included recent developments of new anti-tumor agents specifically targeting death receptor-mediated apoptosis signaling pathways. Upon binding to their cognate receptors death ligands induce apoptotic death of responsive cells. Scientists and physicians now see new therapeutic options of death ligands in selectively driving tumor cells into apoptotic cell death. In this workshop a variety of innovative strategies were presented including the design of single-chain apoptotic ligands linked to antibody fragments recognizing and binding to tumor cell specific target proteins. A different strategy provided optimized death ligands which selectively recognize single members of the TRAIL receptor family, thereby rendering TRAIL-resistant cancer cells responsive to the treatment. Antibodies engineered to bi-specific “diabodies” were shown to selectively target cytotoxic T-cells to tumor cells for killing. Alternatively, tumorselective antibody fragments can be integrated into vesicular structures which contain either chemotherapeutic drugs or death ligand-covered nanoparticles to guarantee target specific delivery.

In a translational approach, new methods for monitoring treatment response of cancer patients were discussed. The therapeutic response is routinely evaluated by imaging methods (ultrasound, computer tomography) which, however, are not able to identify non-responders at an early stage and might therefore allow for further tumor progression. Furthermore, serum biomarkers that could predict the chemotherapeutic outcome in shorter intervals are far from being established. The lack of appropriate methods for closely monitoring the chemotherapy response can result in prolonged ineffective treatment of patients. This does not only cause enormous costs, it also results in unnecessary side effects of patients who might otherwise benefit from alternative treatment regiments. At this workshop novel bioassays for the detection of apoptosis/necrosis in serum samples of cancer patients were presented. These markers might help to identify non-responding tumor patients, who might be prevented from the undesired effects of an ineffective chemotherapy and might benefit from alternative anticancer therapies.

Altogether, this workshop, and also its informal part, fostered new collaborations and research proposals between leading European scientists working on cell death in diseases. The relaxing and inspiring atmosphere at Villa Vigoni contributed to lively round table discussions and stimulated planning of scientific follow-up meetings.

¹Dagmar Kulms, ²Martina Müller and ³Heike Bantel

¹Institute of Cell Biology and Immunology, University of Stuttgart, Germany

²Department of Gastroenterology, University Hospital, Heidelberg, Germany

³Clinic of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

 
The meeting was financially supported by ENZO Life Science AG,

Lausen, Switzerland and PEVIVA, Bromma, Sweden