Abstract
Professor Michael P Schön (University of Würzburg) was interviewed by Emma Quigley (Commissioning Editor, Expert Opinion) on 17th October 2006.
Professor Michael P Schön currently holds the position of Professor of Dermatology and Experimental Biomedicine at the University of Würzburg. He received his MD degree in 1992 from the University of Ulm in Germany. His internationally successful scientific career has led him to study dermatology and immunology at the University of Berlin, Harvard Medical School, the University of Düsseldorf and the University of Magdeburg. With various research awards and certificates in dermatology, immunology and dermatopathology, Professor Schön has published > 100 papers. He has also been a guest editor and on the Editorial Board of various publications.
1. Can you explain the function of cell adhesion molecules?
Cell adhesion molecules play important roles in normal as well as pathophysiological functions of cells, which depend on communications of these cells with other cells or with the extracellular matrix. These important functions include organogenesis during development or maintenance of tissue integrity or immune surveillance under normal conditions. On the other hand, adhesion molecules are crucially involved in pathophysiological processes such as recruitment of immune cells to inflamed tissues and organs or, for example, in autoimmune inflammatory disorders; they are also involved in tumour progression and metastasis formation. Many, if not all, of the adhesion molecules link to intracellular signalling cascades, which then contribute to regulation of other important functions such as cell growth, motility and differentiation. In addition, the activity of adhesion molecules is regulated by a variety of mediators, such as cytokines and chemokines and their receptors; so there is quite an intensive cross talk on a molecular level, between adhesion molecules and other compounds.
In general there are four major classes of adhesion molecules: the first is the cadherin class, the prime example being E-cadherin which primarily functions as a homotypic and homophilic adhesion molecule, which glues together like cells, such as epidermal keratinocytes and other epithelial cells, through interactions with other E-cadherin molecules. There are other members of the cadherin family, whose adhesive functions are usually calcium-dependent, that make connections to intracellular adaptor and signalling molecules.
The second large family is integrins, which are heterodimeric, transmembrane adhesion molecules, which are composed of one α- and one β-subunit. The subfamilies are named after the β-subunit. The different α- and β-subunits make up > 20 different heterodimeric molecules. These integrins have their name because they integrate extracellular molecules with cytoskeletal components. They are also important signal transducers. Their ligands are usually members of the Ig-like superfamily of adhesion molecules or extracellular matrix molecules.
The largest family of adhesion molecules is the Ig-like molecules, which comprises > 200 members at this time. They are usually single-chain transmembrane molecules which are involved in a multitude of normal and pathological cellular functions.
The smallest family is the selectins; we only know of three selectins. L-selectin is expressed on leukocytes and E- and P-selectin are expressed on endothelial cells. These molecules are mostly involved in leukocyte recruitment in inflammation; they also play a role in tumour metastasis.
2. What are the therapeutic implications of targeting cell adhesion molecules?
The therapeutic implications follow immediately from the pathophysiological processes that adhesion molecules are involved in. It is conceivable that these effects are translated into clinical applications to treat chronic inflammatory and autoimmune diseases. An example of this is efalizumab, an antibody that blocks the function of an integrin adhesion receptor, which has been approved for psoriasis, one of the most common chronic inflammatory skin disorders in humans. Integrin-directed compounds and some adhesion molecules of the Ig-like superfamily have also been pursued for the treatment of malignant tumours.
However, in that respect one has to keep in mind that several approaches which selectively target adhesion molecule functions have been discontinued or were not convincing in clinical trials. This highlights an important issue of cell adhesion molecule-directed therapy, namely quite remarkable redundancy and overlapping functions of adhesion molecules. An illustrative example may be the selectin family. The blockade of single selectins by, for example, antibodies did not result in clinical improvement of inflammatory conditions such as psoriasis.
To me it appears that targeting adhesion molecule functions may in some cases be successful as a monotherapy like efalizumab, but in other cases might be better suited within regimens in which several players in pathogenic cascades are targeted.
3. What are you currently working on?
We are working on two focus areas. The first is centred on the molecular basis of immune cell recruitment during inflammatory reactions. Being a dermatologist by training, I am primarily using inflammatory skin diseases as model disorders. In this field we work on the role of selectins for leukocyte–endothelial cell interactions and the functions of some integrins for epithelial localisation of lymphocytes. In our second scientific focus we investigate adhesive interactions of tumour cells with vascular endothelium and their involvement in metastasis formation and adhesion molecules mediating these interactions. We also study tumour cell progression and the mode of action of small-molecule antitumoural therapeutics.
We have several collaborations in both research areas, not only with academic institutions but also with the pharmaceutical and biotech industry. The Rudolf Virchow Center for Experimental Biomedicine, an Institute funded by the German Research Foundation, provides a vibrant and stimulating platform for our research.
4. Are there any therapies that currently target adhesion molecules?
There are some examples of drugs that have either been approved for clinical use or are in clinical or preclinical development. I have already mentioned efalizumab which targets the CD11a/CD18 (LFA-1) adhesion receptor; this compound has been approved for treatment of psoriasis. Another example is natalizumab, an antibody that targets the α4β1 (VLA-4) integrin. It was originally approved for treatment of multiple sclerosis but was recently withdrawn from the market due to severe and unexpected neurological side effects in some patients. This example vividly illustrates that we still have much to learn about the mode of action of adhesion molecule-directed therapeutics. There is a number of other adhesion molecule-directed compounds that have been evaluated in clinical trials, such as selectin-directed antibodies and antibodies directed against intercellular adhesion molecule-1 (ICAM-1) and other Ig-like molecules. Relatively few have made their way to the market so far.
Small-molecule drugs may be advantageous in some aspects compared with antibodies because you can potentially administer them orally and some of them have a broader spectrum of actions. For example, several small-molecule selectin antagonists block all three selectins, which may be beneficial when it comes to clinical applications where there are considerable overlaps between selectin functions that may compensate for each other. However, none of these small-molecule antagonists have been approved for clinical use so far.
One reason for that may be because you can target an antibody more specifically to a given molecule and antibody technology has advanced quite a bit over the past few years so several of these humanised, or fully human, antibodies have made their way to the late stages of clinical trials, or have been approved for the treatment of inflammatory disorders.
5. What is the mechanism of antibodies blocking adhesion molecules?
It is rather straightforward; they either target adhesion molecules at epitopes that are not related to the ligand binding site and by doing this, they alter the conformation or the state of activation of the adhesion molecules. You can do this with integrins. Or you can target the ligand binding site and thereby directly interfere with ligand binding and consequently signal transduction of the adhesion receptor.
6. What is their role in inflammation?
To understand the role of adhesion molecules in inflammation, we have to understand how inflammation, in general, works. It largely depends on the recruitment of immune cells to sites of inflammation. This is a multistep process governed by different adhesion molecules but also by tightly interacting molecules of other families, such as cytokines, chemokines, chemokine receptors and so on. In general, recruitment of inflammatory cells begins with rolling along the endothelial wall, which slows cells down from the blood flow. This process is mediated by selectins and, to some extent, the VLA-4 integrin. The initial contact is transient and is replaced by firm adhesion, which follows activation of the immune cells through chemokine receptors and this is mediated by integrins, primarily. There is then a transmigration of immune cells through the endothelial lining; a process that involves integrins and a number of Ig-like adhesion molecules, such as members of the JAM family (junctional adhesion molecules). It is conceivable to interfere with this cascade of events at several different steps. I have already mentioned efalizumab which targets firm adhesion of lymphocytes to activated endothelia.
Natalizumab targets VLA-4, a molecule involved in two or three separate steps in inflammation. It contributes to rolling of leukocytes but also mediates firm adhesion through interaction with VCAM-1.
7. Are any cell adhesion molecules implicated in cancer progression?
Sometimes the role of adhesion molecules in cancer biology is not that easy to grasp. The specific contribution of a given adhesion molecule may depend on various factors such as tumour type, composition of the tumour-surrounding microenvironment and other factors. In general, in order to spread a tumour cell needs to disrupt adhesive interactions to leave the tissue of origin and then migrate through the extracellular matrix. Tumour cells that successfully progress and metastasise need to establish new adhesive interactions with endothelial cells or other cell types or extracellular matrix, which enable them to adhere and transmigrate through the vascular wall. Therefore, it becomes quite readily apparent that complex regulations of adhesion molecule functions contribute to tumour progression. This illustrates the central role of adhesion receptors in tumour biology. One of the most extensively studied examples of adhesion molecules is E-cadherin, whose essential role in the formation and maintenance of epithelial tissues has long been recognised. E-cadherin is particularly interesting as it appears to exert different functions that may be important in tumour biology. The loss of the homotypic and homophilic functions of E-cadherin are thought to result in impaired tissue integrity and the ability of tumour cells to leave their tissue of origin, therefore, promoting local tumour progression and metastasis formation. It is not currently clear if and how the heterotypic or heterophilic adhesive function of E-cadherin, which for example contributes to the adhesion of antigen-presenting cells in the epidermis or to the recruitment of intra-epithelial T lymphocytes through interactions with the αEβ7 integrin, contributes to immune escape mechanisms of some tumours.
The second point about E-cadherin is that the diminished surface expression of E-cadherin in tumour cells is associated with altered signalling function of one of its intracellular binding partners, β-catenin, this molecule then contributes to the deregulated transcription of several tumour progression-associated gene products.
The selectin family appears to contribute to metastasis of several tumours, either through mediation of direct endothelial cell–tumour cell interaction or indirectly through the generation of aggregation of tumour cells with leukocytes or platelets. This facilitates interactions with endothelial cells which ultimately results in enhanced metastasis formation. The role of selectins for tumour progression has been highlighted by selectin-deficient mice, which show reduced formation of tumour metastasis under experimental conditions. There are also several adhesion molecules that have been implicated in tumour angiogenesis, such as β3 integrins. There have been a number of preclinical experimental approaches in which specific inhibition of the function of adhesion molecules, such as integrins or Ig-like adhesion molecules, has resulted in diminished tumour progression. Thus, far, broader introduction of such principles into the clinic has been hampered by the sheer complexity and some redundant and overlapping regulation and function of adhesion molecules.
8. Can you explain the association between cell adhesion molecules and dermatological disorders?
There are a number of chronic inflammatory skin disorders that largely depend on the recruitment of immune cells to inflamed skin. The pathogenic cascades that we have already outlined critically contribute to the generation and maintenance of these disorders, which include common diseases such as psoriasis, atopic dermatitis or cutaneous lupus erythematosus.
The other issue is, of course, skin cancer. Many of the features that we know about tumour biology and the role of adhesion molecules in tumour biology actually comes from knowledge of skin cancer, such as squamous cell carcinoma, basal cell carcinoma and malignant melanoma. For example, the loss of E-cadherin function has been extensively studied in squamous cell carcinomas of the skin.
9. What is the future for research into adhesion molecules?
I think we need to better understand the molecular crosstalk between adhesion molecules and other cells in normal and pathological conditions. These interactions include modulation of adhesion molecule expression and function, as well as signal transduction pathways. I believe a better understanding of these interactions will allow two things:
| • | It will permit to identify groups of target molecules that act synergistically and/or in redundant systems, whose actions could then be blocked simultaneously perhaps in therapeutic approaches to specific disorders. | ||||
| • | It will allow us to specifically target several steps in a chain or cascade of molecular events that eventually result in a pathological condition. For example, if you simultaneously target the adhesion molecule and the downstream signalling event you might have a better result overall. | ||||
10. Please provide your expert opinion
What we have learned over the past years is that cell adhesion mechanisms involved in the pathogenesis of diseases appear to be much more complex and intertwined than previously thought. Adhesion molecules function or interact directly or indirectly with many molecules involved in other cell functions, including signal transduction molecules, transcription factors and receptors. Personally, I hope that we will be able in the future to specifically modulate adhesion molecule functions in the context of broader therapeutic regimens, such as part of combination therapies to improve the prognosis of malignant or inflammatory disorders. However, in the past, overenthusiastic hopes have been dampened, probably due to oversimplification of molecular mechanisms. A reasonable assumption may be that modulating certain adhesion molecules could be part of a larger mosaic of complimentary mechanisms, and in this context targeting adhesion molecule functions may indeed hold some promise for the future.
Contact details
Michael P Schön can be contacted at the Rudolf Virchow Center for Experimental Biomedicine and Department of Dermatology, Venereology and Allergology, University of Würzburg, Germany, by telephone (+49 931 201 48977) or by email ([email protected]).