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: 7787632
• 负责人: REBECCA Jane MORRIS
• 金额: $ 19.54万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787632
• 关键词: Address; Annexins; Antibodies; Apoptosis; Apoptotic; Benign; Bone Marrow; Bone Marrow Cells; 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; Hand; 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（由申请方提供）：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，这一点已通过流行病学证据以及人类癌症发展与UVB引发癌症的小鼠模型之间的密切相关性得到证实。虽然UVB诱导的皮肤癌被广泛认为起源于表皮或毛囊干细胞的转化，但最近证明胃癌起源于骨髓衍生细胞（BMDCs）挑战了这一教条。这项研究的目的是确定毛囊干细胞和BMDCs的相对贡献，发展皮肤肿瘤的小鼠UVB模型的皮肤癌。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。我们的方法是将遗传标记的BMDC（“绿色细胞”）移植到致死辐射的Krt 1 - 15 CrePR 1; R26 R雌性小鼠中，所述小鼠在用RU 486诱导后在毛囊干细胞及其后代中表达β-半乳糖苷酶（“蓝色细胞”）。在慢性UVB暴露期间，我们将在皮肤切片和从皮肤和肿瘤收获的细胞制剂中评估供体来源的细胞（表达EGFP和Y染色体）与毛囊干细胞来源的上皮病变。然后，我们将确定这两个群体的关系，突变p53补丁的发展，以及威尔斯他们的关系，凋亡小体（晒伤细胞）和其他标志物的细胞死亡。这些实验不仅将确定BMDC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以及如何诊断和治疗这些癌症的想法。 公共卫生相关性：皮肤长期暴露于阳光（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，但最近的一份报告称胃癌可能起源于骨髓来源细胞的转化，这一教条受到了挑战。本文提出的研究目的是确定骨髓源性细胞和毛囊干细胞及其后代在小鼠UV皮肤癌模型中发展皮肤肿瘤的相对作用。这项研究的方法和结果与人类健康有关，因为它们不仅将确定骨髓源性细胞和毛囊干细胞对皮肤癌的各自贡献，而且还将有可能改变目前对皮肤癌诊断和治疗方式的看法。