The Role of Bone Marrow Derived Cells in Skin Cancer

骨髓来源细胞在皮肤癌中的作用

• 批准号: 8016702
• 负责人: REBECCA Jane MORRIS
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016702
• 关键词: Address; Annexins; Antibodies; Apoptosis; Apoptotic; Benign; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; CD34 gene; Carcinoma; Cell Death; Cells; Characteristics; Chronic; Clinic; Cutaneous; Development; Diagnosis; Epidemiology; Epidermis; Epithelial; Event; Exposure to; Female; Fluorescent Antibody Technique; Hair follicle structure; Harvest; Health; Human; Immune; Investigation; Keratin; Label; Laboratories; Langerhans cell; Left; Lesion; Malignant - descriptor; Malignant Neoplasms; Maps; Methods; Modeling; Mus; Neoplasms; Papilloma; Pattern; Population; RU-486; Recruitment Activity; Relative (related person); Reporting; Research; Role; Science; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Staging; Staining method; Stains; Stem cells; Stomach; Sunburn; Sunlight; T-Lymphocyte; TP53 gene; Thinking; Tissues; Transgenic Mice; Transplantation; Tumor Stem Cells; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Y Chromosome; beta-Galactosidase; cancer diagnosis; carcinogenesis; cell preparation; immunoreactivity; irradiation; keratinocyte; killings; malignant stomach neoplasm; mouse model; mutant; novel; public health relevance; recombinase; reconstitution; research study; skin lesion; tumor

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.

描述（由申请人提供）：流行病学证据证明，皮肤长期暴露于紫外线（UVB）是导致非黑色素瘤皮肤癌的主要原因，人类癌症发展与UVB引发癌症的小鼠模型之间存在密切相关性。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，但最近的研究表明胃癌起源于骨髓来源细胞（bmdc），挑战了这一教条。本研究的目的是确定毛囊干细胞和BMDCs在小鼠UVB皮肤癌变模型中发生皮肤肿瘤的相对贡献。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。我们的方法是将基因标记的BMDCs（“绿色细胞”）移植到致命照射的Krt1-15CrePR1；在RU486诱导下，在毛囊干细胞及其后代中表达β -半乳糖苷酶的R26R雌性小鼠（“蓝色细胞”）。在慢性UVB暴露期间，我们将评估皮肤切片中供体来源的细胞（表达EGFP和Y染色体）与毛囊干细胞来源的上皮病变，以及从皮肤和肿瘤中收获的细胞准备。然后，我们将确定这两个种群与突变p53斑块发育的关系，以及它们与凋亡小体（晒伤细胞）和其他细胞死亡标志物的关系。这些实验不仅将确定BMDCs和毛囊干细胞对肿瘤发展的各自贡献，还将为确定皮肤肿瘤起始细胞与肿瘤干细胞的关系奠定基础。这些实验也有可能改变目前对皮肤癌发展机制的看法，以及如何诊断和治疗这类癌症。