The Role of Bone Marrow Derived Cells in Skin Cancer

描述(申请人提供)：皮肤长期暴露于紫外线(UVB)是非黑色素瘤皮肤癌的主要已知原因，流行病学证据以及人类癌症发展与UVB引发的癌症小鼠模型之间的密切相关性证明了这一点。虽然人们普遍认为UVB诱导的皮肤癌起源于表皮或毛囊干细胞的转化，但最近的证据表明，胃癌起源于骨髓来源的细胞(BMDCs)挑战了这一教义。本研究的目的是确定毛囊干细胞和骨髓间充质干细胞在UVB皮肤癌变模型小鼠皮肤肿瘤发生中的相对作用。我们的假设是毛囊干细胞和BMDCs都是皮肤癌发生和发展的重要靶细胞。我们的方法将是将基因标记的BMDCs(“绿色细胞”)移植到经致死照射的Krt1-15CrePR1；R26R雌性小鼠，这些小鼠在毛囊干细胞及其后代中表达β-半乳糖苷酶，经RU486(“蓝色细胞”)诱导后。在慢性UVB照射期间，我们将评估皮肤切片和从皮肤和肿瘤采集的细胞制剂中供体来源的细胞(表达EGFP和Y染色体)与毛囊干细胞来源的正在发生的上皮损伤。然后我们将确定这两个群体与突变型P53斑块的发展的关系，以及它们与凋亡体(晒伤细胞)和其他细胞死亡标志的关系。这些实验不仅将确定BMDCs和毛囊干细胞在肿瘤发生中的各自作用，还将为确定皮肤肿瘤启动细胞与肿瘤干细胞的关系奠定基础。这些实验还有可能改变目前人们对皮肤癌发生机制以及如何诊断和治疗皮肤癌的看法。 与公共健康相关：皮肤长期暴露在阳光下(紫外线)是皮肤癌的主要已知原因。虽然紫外线诱导的皮肤癌被广泛认为起源于表皮或毛囊干细胞，但最近的一份报告表明，胃癌可以起源于骨髓来源的细胞的转化，这一教条对此提出了挑战。本研究的目的是确定骨髓来源细胞和毛囊干细胞及其后代在小鼠紫外线皮肤癌模型中发生皮肤肿瘤的相对作用。这项研究的方法和结果与人类健康相关，因为它们不仅将确定骨髓来源细胞和毛囊干细胞在皮肤癌中各自的贡献，而且它们还有可能改变目前临床上诊断和治疗皮肤癌的方式。

DESCRIPTION (provided by applicant): Chronic exposure of the skin to ultraviolet light (UVB) is a major known cause of nonmelanoma skin cancer as demonstrated by epidemiological evidence and by the tight correlation between cancer development in humans and that of the mouse models of UVB-initiated cancer. Although UVB-induced skin cancers are widely believed to originate from the transformation of epidermal or hair follicle stem cells, recent demonstration that gastric cancer originates from bone marrow derived cells (BMDCs) challenges this dogma. The objective of this proposed investigation is to determine the relative contributions of hair follicle stem cells and BMDCs to developing skin tumors in the mouse UVB model of cutaneous carcinogenesis. Our hypothesis is that both hair follicle stem cells and BMDCs are important target cells in skin cancer development and progression. Our method of approach will be to transplant genetically labeled BMDCs ("green cells") to lethally irradiated Krt1-15CrePR1;R26R female mice that express beta- galactosidase in hair follicle stem cells and their progeny following induction with RU486 ("blue cells"). At intervals during chronic UVB exposure, we will then assess developing epithelial lesions for cells of donor origin (expressing EGFP and the Y chromosome) vs. hair follicle stem cell origin in skin sections and harvested cell preparations from skin and tumors. Then we will determine the relationship of both of these populations to the development of mutant p53 patches, as wells their relationship to apoptotic bodies (sunburn cells) and other markers of cell death. These experiments will not only determine the respective contributions of BMDCs and hair follicle stem cells to developing tumors, they will also set the stage for defining the relationship of skin tumor initiating cells to tumor stem cells. These experiments also have the potential to change current thinking on the mechanisms of skin cancer development and how such cancers are diagnosed and treated. PUBLIC HEALTH RELEVANCE: Chronic exposure of the skin to sunlight (UV light) is a major known cause of skin cancer. Although UV-induced skin cancers are widely believed to originate from epidermal or hair follicle stem cells, a recent report that stomach cancer can originate from the transformation of bone marrow derived cells challenges this dogma. The objective of the research proposed here is to determine the relative roles of bone marrow derived cells and hair follicle stem cells and their progeny to developing skin tumors in the mouse UV model of skin cancer. The approach and results of this study are relevant to human health in that they will not only determine the respective contributions of bone marrow derived cells and hair follicle stem cells to skin cancer, they will also have the potential to change current thinking on the way that skin cancer is diagnosed and treated in the clinic.