The incidence of skin carcinomas has been rising over the last decades. Ultraviolet (UV) radiation from the sun is the main exogenous risk factor. The principal premise underlying the present... Show moreThe incidence of skin carcinomas has been rising over the last decades. Ultraviolet (UV) radiation from the sun is the main exogenous risk factor. The principal premise underlying the present study is that stem cells are the primary targets of UV carcinogenesis. The aim of this study was to identify the main (stem) cell pool that drives this skin carcinogenesis. We studied cells in the interfollicular epidermis (IFE), quiescent stem cells and actively cycling Lgr5+ and Lgr6+ cells. Our data indicated that UV induced squamous cell carcinomas originate from the IFE. Furthermore, quiescent stem cells seem to play an important role in skin carcinogenesis. These cells accumulate DNA damage under chronic low level UV exposure. When we forced these DNA-damage retaining cells to proliferate, persistent (in situ) carcinomas developed. The actively cycling Lgr5+ and Lgr6+ cells did not seem to entail tumor-initiating stem cells in skin tumors induced by UV radiation or chemicals. We did not observe any tumors with substantial clonal expansion of Lgr5+ or Lgr6+ stem cells. Taken together, these results indicate that the continuously proliferating Lgr5+ and Lgr6+ stem cells are less vulnerable to cancerous transformation than quiescent stem cells. Show less
Glind, G. van de; Rebel, H.; Kempen, M. van; Tensen, K.; Gruijl, F. de 2016
Skin cancer is a serious problem for many organ transplant recipients. Half of them develop skin cancer within 20 years after the transplantation. The main cause of this increased skin cancer risk... Show moreSkin cancer is a serious problem for many organ transplant recipients. Half of them develop skin cancer within 20 years after the transplantation. The main cause of this increased skin cancer risk is thought to be suppression of the immune system, a necessity to prevent rejection of the transplanted organ. This thesis focuses on the effects of immunosuppressive drugs on the responses of skin cells to UV irradiation and how these altered responses would affect UV-induced skin cancer development. The goal was to compare several immunosuppressants and identify the least hazardous one. Human skin cultures and mice were used as experimental models to study short and long term effects in successive stages of tumor development. These studies have yielded several unexpected findings. Foremost, none of the tested immunosuppressants increased skin cancer development in mice when administrated in the diet; remarkably, cyclos porin even delayed tumor onset. And furthermore, seemingly discordant effects of the drugs on different putative stages of tumor development evoked a new perspective on the step-wise process leading up to skin cancer. More specifically and contrary to the prevailing consensus, this study showed that UV-induced early microscopic clusters of skin cells overexpressing the mutant-p53 tumorsuppressor protein are not early stages or precursors of ensuing skin carcinomas with mutant-p53. Surprisingly, some immunosuppressants affected the number of these clusters without corresponding effects on tumor onset. Show less
