MADRID — The Nobel Prize-winning discovery of aquaporins is having a trickle-down translational effect that could have a major impact upon the prevention and treatment of both melanoma and nonmelanoma skin cancers.
Aquaporins (AQPs) are also actively under study for potential utility in the treatment for a range of other diseases, including epilepsy, obesity, severe heart failure and various other edematous states, malaria, wound healing, glaucoma, Sjögren's syndrome, and for neuroprotection after brain or spinal cord injury, Dr. Julián S. Conejo-Mir said at the 13th World Congress on Cancers of the Skin, sponsored by the Skin Cancer Foundation.
Dr. Julián S. Conejo-Mir
There are also potential diagnostic applications, Dr. Conejo-Mir noted. The prototype is the discovery that AQP4 autoantibodies serve as a marker allowing for precise diagnosis of the neuromyelitis optica variant of multiple sclerosis.
However, while AQPs are now understood to have major influence in a wide range of diseases, no suitable AQP-modulator drugs have been identified.
Mercury and gold are pan-AQP inhibitors, but they are toxic and impractical in a therapeutic context, he noted. "It's early days," said Dr. Conejo-Mir, professor of dermatology at the University of Seville, Spain.
Aquaporins are a family of small cell membrane proteins that facilitate water transport in animals and plants. Thirteen mammalian AQPs have been identified. Dr. Peter C. Agre, the immediate past-president of the American Association for the Advancement of Science and a physician at Johns Hopkins University, Baltimore, who shared the 2003 Nobel Prize in Chemistry for his discovery of AQPs, called them "the plumbing system for cells."
AQP1 and AQP3 appear to be particularly relevant in skin cancer. They are involved in the key processes of cell migration, angiogenesis, cellular proliferation, and metastasis, said Dr. Conejo-Mir.
He presented a study in which he obtained 4-mm punch biopsies from 32 patients with various types of melanocytic skin lesions: 20 with malignant melanoma, 7 with common-acquired melanocytic nevi, and 5 with atypical or dysplastic nevi. The tissue specimens then underwent immunohistochemical staining for AQP1 and AQP3.
AQP1 was strongly expressed in the common melanocytic nevi but absent in the dysplastic nevi and all types of melanoma, which included six specimens of superficial spreading, four acral, five nodular, and five lentigo maligna melanomas.In contrast, AQP3 was upregulated in all of the melanocytic lesions, malignant or benign.
Dr. Conejo-Mir noted that his findings were consistent with prior studies by Dr. Alan S. Verkman and coworkers, who have done much of the early research on the role of AQPs in skin cancer.
AQP3 belongs to an AQP subgroup known as aquaglyceroporins, which transport glycerol as well as water. Dr. Verkman, who is professor of medicine and physiology at the University of California, San Francisco, and coworkers reported that AQP3 is normally expressed in plasma membranes of the basal epidermal cell layer of mammalian skin and is strongly overexpressed in human squamous cell carcinoma. They also demonstrated that AQP3-deficient mice have pathologically dry skin and slow recovery of the skin's barrier function after damage to the stratum corneum.
Dr. Verkman also found that AQP3-deficient mice are highly resistant to development of skin tumors when subjected to the standard multistage skin-tumor induction protocol widely utilized by bench scientists to study skin carcinogenesis.
"The remarkable resistance to skin tumorigenesis in AQP3 deficiency provides a rational basis for evaluation of AQP3 inhibitors for prevention and therapy of skin and other tumors associated with AQP3 overexpression," according to Dr. Verkman and Mariko Hara-Chikuma, Ph.D. (Mol. Cell. Biol. 2008;28:326-32).
The key roles AQPs play in glandular fluid secretion and urinary concentration were predictable based upon AQPs' function in transepithelial fluid transport. What was unanticipated, however, was aquaglyceroporins' involvement in fat metabolism, skin hydration, carcinogenesis, neural activity, and ocular function, which may mean translational possibilities for new treatments (J. Exp. Biol. June 2009; 212:1707-15).
Dr. Conejo-Mir had no conflicts of interest to disclose.