Background
Background
During the past decade apoptosis has been established as a process of crucial importance in maintaining the normal homeostasis in developing and adult tissues. Consequently, many important human diseases result from an imbalance between cell proliferation and cell death. It has been shown that insufficient cell death leads to diseases such as cancer, where the tumors arise and progress as a result of inhibition of apoptotic cell death. Conversely, often in situations of stress, for example during insufficient blood flow (ischaemia) to organs, the initial damage is dramatically boosted through the activation of an endogenous apoptotic cell suicide reaction. Erroneous activation of apoptosis leads to degeneration of functional tissue, an effect which is typically observed in infarct and stroke with severe consequences to organs like heart, brain, and liver.
It is not surprising that apoptosis research has uncovered a novel paradigm for the treatment of disease. The laboratories of this consortium actively pursue (i) novel approaches to study apoptosis and (ii) novel strategies to identify therapeutic measures to modulate apoptosis. The strategy for modulation of apoptosis is based on: (A) targeting drugs to anti-apoptotic signaling modules, and (B) targeting drugs to the expression of anti-apoptotic heat shock proteins. These approaches will be applied to diseases resulting from impaired apoptosis (e.g., cancer, autoimmune diseases) or diseases resulting from excessive apoptosis (e.g., ischaemic damage, drug-induced injury, age-induced tissue degeneration). These diseases represent strategic therapeutic areas to the commercial partners involved in this consortium.
Growth factor signaling pathways that inhibit apoptosis
We have observed that many tumor cells are totally insensitive towards apoptosis induction through the major physiological pathway, the stimulation of Fas receptor. Recently our work has established that the mitogen-activated protein kinase (MAP kinase), the major oncogenic signaling pathway, is in many tumor cells responsible for this insensitivity. These findings clearly demonstrate that signaling molecules are very promising and important targets when the goal is to modulate the rate of apoptosis.
Fig. 1. Tumor cells that can be sensitized to receptor-mediated apoptosis by inhibiting a single signaling module. When the Fas receptor is stimulated in HeLa cells (middle picture), there is no significant apoptosis as compared to control cells (left picture), as shown by thenormal nuclear morphology. When cells have been preincubated with a MAP kinase inhibitor (PD 98059), most of the Fas receptor-stimulated cells undergo apotosis (right hand picture), as indicated by the brightly stained apoptotic nuclei. This approach, using a non-sensitive cell lineto test for faciliation of apoptosis will be used as a major screen. It is an example of how a pharmacological agent targeted at a single signaling module could be used in cancer therapy to sensitize tumor cells to apoptotic depletion by T-cells and during cancer chemotherapy.
Cellular heat shock responses as regulators of apoptosis
All organisms share a common molecular response to physiological stress conditions, which is characterized by a dramatic change in gene expression leading to elevated synthesis of a family of heat shock or stress-induced proteins, Hsps. These proteins, which are also induced under certain non-stressful conditions, such as differentiation and growth, are mainly regulated at the transcriptional level by specific heat shock transcription factors, HSFs. Expression of Hsps has been shown to protect cells from the environmental stress damage, and recently, evidence for their interaction with the apoptotic pathways has emerged. For instance, elevated synthesis of Hsp70 is a potent negative regulator of apoptosis induced by TNF, heat stress, and cytostatic drugs. A mild stress, which induces synthesis of Hsps, will enable cells to survive a significantly stronger stress later on, and, therefore, induction of Hsps can be used to promote survival of stressed cells. This response may be beneficial in many disease conditions (ischaemia, stroke, reperfusion, intoxication, neurodegeneration) but may also be detrimental to, for example chemotherapy, as it will make tumor cells more resistant towards cancer therapy. Therefore the identification and modulation of stress responses and HSFs expression will be important in the development of future therapeutic strategies, as envisaged by the Commercial Partners.