Dissecting microenvironmental factors, genetic alterations

Philadelphia - There are multiple steps and mechanisms necessary for carcinogenesis, including multiple genetic alterations that cause an initiation phase, as well as microenvironmental factors that contribute to a promotion phase and a progression phase of a skin cancer.

Xiao-Jing Wang, M.D., Ph.D., director of the department of molecular biology - head and neck cancer research and professor of the departments of dermatology, otolaryngology and cell and developmental biology at Oregon Health and Science University, Portland, Ore., offered her experience and insight in molecular biology and skin cancer and spoke of her latest research on skin carcinogenesis, at the 2006 annual meeting of the Society for Investigative Dermatology, here.

Nonmelanoma skin (NMSC) cancer is the most common cancer in the United States, with squamous cell carcinomas (SCC) accounting for 20 percent and basal cell carcinomas (BCC) accounting for 80 percent of these cancers.

It is within the keratinocytes where the genetic alterations lie and ultimately cause the skin cancer, with ultraviolet irradiation being the major culprit and environmental carcinogen.

Dr. Wang says that multiple genetic alterations are required for cancer formation and its progression. Also, the status of the microenvironment is of paramount importance in carcinogenesis, and an inflammatory and angiogenic microenvironment is necessary for the malignant progression of a tumor. One example she gave was that the administration of immunosuppressants in transplant patients can increase the incidence of SCCs up to 60 times more than that of the general population.

A main focus of Dr. Wang and her researcher team is the function of transforming growth factor beta (TGF-beta) signalling in carcinogenesis, wound healing, skin/appendage development and diseases. TGF-beta is a multifunctional cytokine that is crucial for the maintenance of epithelial homeostasis. Her laboratory developed inducible and epithelial-specific transgenic/knockout mouse models (gene switch) that permit the examination of the functions of TGF-beta signalling components at specific stages during carcinogenesis, as well as in wound healing and skin/appendage development.

Dr. Wang says, "Alterations in the TGF-beta signal transduction pathway at any level including the ligand, receptor and signalling mediator (Smads), lead to a higher susceptibility to cancer. Applying chemical carcinogenesis protocols to mouse skin allows tumorigenesis to develop in the discrete stages of initiation, promotion and malignant conversion. After the tumors are elicited, we induce TGF-beta-1 expression in gene-switch-TGF-beta-1 mice at different stages. These experiments allow us to determine the roles of TGF-beta in different stages of skin carcinogenesis and to analyze the underlying molecular mechanisms of TGF-beta functions in carcinogenesis."

Smad functions

According to Dr. Wang, Smad family members have two very important functions.

They are responsible for mediating TGF-beta signalling for both tumor suppression and tumor promotion. Research has shown that mutations of Smads exist in various human cancers, implying that the loss of Smads may also lead tumor cells to develop resistance to TGF-beta-induced growth inhibition. The researcher confirms that the loss of Smad4 correlates with malignant conversion during skin carcinogenesis. However, the researcher has also shown that loss of Smad3 results in a resistance to skin cancer formation.

Dr. Wang speculates that, "The combination of targeting tumor epithelia and controlling the effect of TGF-beta-1 on tumor stroma may provide a more efficient therapy for cancer."