Cutaneous blood, lymph vessels present new therapeutic targets

National report - Basic science research focusing on the role of the cutaneous vasculature in skin disease has provided new insights regarding pathogenesis and therapy, Michael J. Detmar, M.D., says.

He was honored as the 2005 recipient of the Marion B. Sulzberger Memorial Award Lectureship at the 63^rd Annual Meeting of the American Academy of Dermatology. He described for attendees the findings from his investigations in the field of cutaneous vascular biology and their implications for management of psoriasis, melanoma and other cancers.

Dr. Detmar notes that although studies to elucidate the mechanisms for psoriasis development have predominantly focused on the role of the epidermis and the immune system, more recent evidence implicates the importance of the vascular system.

Based on findings from a variety of animal and clinical studies conducted in his own laboratory and by other researchers, Dr. Detmar proposed that psoriasis develops over time as a result of upregulation of vascular endothelial growth factor (VEGF) expression in the epidermis and the subsequent induction of angiogenesis. That theory is the basis for ongoing research to identify new targeted therapies for psoriasis acting to locally inhibit VEGF activity.

"Extensive vascular proliferation and leakiness is a feature of psoriatic skin, but one that has been overlooked by scientists who have concentrated primarily on the epidermal hyperplasia and inflammatory components in trying to elucidate the pathogenesis of this disease," Dr. Detmar says.

Pioneering work by Irwin Braverman, M.D., who identified that the epidermis in psoriatic skin produces an angiogenic factor, provided the first clue that the blood vessels may play more than just a passive role. Subsequently, Dr. Detmar and colleagues identified that angiogenic mediator as VEGF and showed that it was potently upregulated in psoriatic skin while minimally present in normal tissue.

Mouse model

To investigate whether VEGF was present as a secondary effect or played an active role in disease pathogenesis, transgenic mice were genetically engineered to produce high levels of VEGF in the epidermis.

While those animals were born with normal skin, within six months they spontaneously developed chronic inflamed lesions that were clinically and histologically similar to human psoriasis.

"We even found that we could induce prolonged and persistent inflammation in these animals by the Koebner phenomenon whereas wild-type mice would develop inflammation that was only short-lived," Dr. Detmar reports.

However, treatment with a VEGF-blocking agent resulted in rapid resolution of the inflammation. That observation together with recent findings from genetic studies showing patients with severe psoriasis have a significantly increased frequency of a VEGF gene polymorphism leading to increased circulating VEGF levels provide good evidence that vascular activation plays a role in psoriasis development.

Those studies have generated interest in developing therapeutic strategies for inhibiting VEGF signaling, and Dr. Detmar reports, that success has been achieved so far in animal models using agents that block VEGF activity directly or through its receptors.

Novel melanoma prognostic marker

Findings from research conducted by Dr. Detmar and colleagues have also refuted the longstanding dogma that melanoma cells metastasize to the lymph nodes in a passive process wherein the tumor cells accidentally "happen on" pre-existing lymphatic vessels.

Instead, Dr. Detmar hypothesizes that melanomas can induce lymphatic vessel growth that allows for metastasis to sentinel lymph nodes. Once the tumor cells reach the sentinel node, they can again induce lymphangiogenesis that permits metastasis to more distant lymph nodes and finally to organs.

"Therefore, we would like to block this induction of lymphatic vessel growth in order to prevent or inhibit melanoma metastasis, and initial experiments in animals suggest this might be possible," Dr. Detmar says.

Useful prognostic marker

The studies focusing on melanoma lymphangiogenesis also suggest that identification of lymphatic vessel proliferation may be a useful prognostic marker for predicting later metastasis and disease survival.