The major goal of this grant application is to test a novel hypothesis that age-related changes in the dermal extracellular matrix (ECM) microenvironment promote skin cancer development. Cancer is a disease of aging. For example, keratinocyte skin cancer, the most common form of human cancer, rarely occurs in individuals under the age of 40, but very common in the elderly. The importance of stromal connective tissue microenvironment in epithelial cancer is receiving increased recognition. However, the concept that natural aging brings about changes in the ECM microenvironment that promote cancer development has received little attention. In human skin, dermal fibroblasts are responsible for homeostasis of the collagenous ECM, which comprises the bulk of skin. Our recent studies reveal that aged dermal fibroblasts in vivo, express elevated levels of a protein called CCN1 (first member of CCN family proteins), which is secreted and binds to the dermal ECM. We find that elevated CCN1 up-regulates numerous proteins related to senescence-associate secretory phenotype (SASP), and thus promotes dermal connective tissue aging. These alterations include: 1) reduced levels of collagens, which causes dermal thinning; 2) elevated levels of multiple collagen-degrading enzymes, which cause increased fragmentation of ECM; and 3) increased levels of multiple pro-inflammatory cytokines, which contributes to dermal inflammaging. Importantly, all of these CCN1-indced alterations are readily observed in aged human skin in vivo. Based on these considerations, we have created a transgenic mouse model that expresses CCN1 under control of a fibroblast-specific promoter, the source of elevated CCN1 in aged human skin (col-CCN1TG). These mice display alterations of the dermal ECM microenvironment by secretion of SASP-related genes. In the transgenic mice, skin is thin, finely wrinkled, and collagen fibrils are fragmented and disorganized, as observed in aged human skin. Importantly, these mice display a high propensity for skin tumor formation elicited by two- stage carcinogenesis protocol. Based on these data, we hypothesize that age-associated dermal ECM microenvironment promotes epithelial tumor development. This application will test the above hypothesis using a novel cell-type-specific double-transgenic mouse model, in which the epidermal oncogene Ras is specifically expressed in the skin epithelium and aged-associated dermal ECM microenvironment is generated by fibroblast-specific expression of CCN1. The proposed studies will directly investigate the novel concept that age-associated dermal ECM microenvironment promotes skin cancer development in cooperation with epithelial oncogene, and thus may have profound impact on the field of cancer prevention/treatment in the aged by identifying age-associated dermal microenvironment as a key target for therapeutic intervention.
The bulk of human skin is composed of a collagen-rich extracellular matrix, which is produced, organized, and maintained by fibroblasts in the dermis. The dermal extracellular matrix provides structural and functional support for skin. The goal of this proposal is to investigate the novel hypothesis that age-related alterations of extracellular matrix microenvironment promote skin cancer development. This application will test the above hypothesis using novel cell-type- specific transgenic mouse models, in which aged-related extracellular matrix microenvironment promotes epithelial skin cancer.
