Contribution of resident stem cells to tumor stroma and vasculature

描述（由申请人提供）：癌症干细胞可能构成一种罕见的肿瘤细胞群，具有自我更新和产生大量转化细胞的能力。尽管具有潜在的重要性，但仅靠癌症干细胞无法维持肿瘤组织。包括内皮细胞在内的肿瘤相关基质细胞构成肿瘤组织的重要组成部分，对肿瘤的生长和扩张至关重要。新生血管是一个基本的过程，与干细胞程序密切相关，导致组织生成的生理和病理过程。大量研究表明，绝大多数发生新生血管的内皮细胞来源于非造血干细胞，而不是来源于骨髓的造血干细胞。因此，肿瘤相关基质细胞的很大一部分可能来源于居住在外周组织中的祖细胞。皮肤是人体最大的器官，它含有大量的干细胞，如角质细胞干细胞，参与皮肤的维护和修复。此外，我们假设皮肤中的常驻干细胞在伤口愈合和肿瘤扩张过程中有助于血管和基质的形成。该研究的长期目标是鉴定和表征皮肤中产生肿瘤相关基质细胞（包括内皮细胞）的常驻细胞。为此，我们提出3个具体目标。在具体目标1中，我们将结合谱系和干细胞标记物来定义基质细胞亚群，确定它们的数量和空间分布，并确认它们在肿瘤和邻近皮肤组织中的起源。在特定目标2中，我们将分离基质细胞亚群并根据基因表达模式检查它们的谱系关系。在具体目标3中，我们将确定基质细胞亚群在体内形成血管结构的频率。驻留间质干细胞的鉴定将揭示抑制肿瘤生长的新靶点，为更详细地了解肿瘤和成体干细胞生物学奠定基础，并对促进伤口愈合和组织工程具有重要影响。公共卫生相关性：常驻基质干细胞的鉴定将揭示抑制肿瘤生长的新靶点，为更详细地了解肿瘤和成体干细胞生物学奠定基础，并对促进伤口愈合和组织工程具有重要影响。

DESCRIPTION (provided by applicant): Cancer stem cells may constitute a rare population of tumor cells that has the capacity to self renew and to give rise to the bulk of transformed cells. Despite its potential importance, cancer stem cells alone cannot maintain tumor tissue. Tumor associated stromal cells including endothelial cells constitute a significant fraction of tumor tissue that are critical for its growth and expansion. Neovascularization is a fundamental process that is intimately integrated with a stem cell program leading to tissue generation in both physiologic and pathologic processes. A number of studies have demonstrated that the vast majority of endothelial cells undergoing neovascularization are derived from non-hematopoietic rather than bone marrow derived hematopoietic stem cells. A significant fraction of tumor-associated stromal cells may therefore be derived from progenitors that reside in peripheral tissue. The skin, the largest organ, contains a number of stem cells such as keratinocyte stem cells that participate in its maintenance and repair. In addition, we hypothesize that as yet poorly characterized resident stem cells in the skin contribute to vessels and the stroma during wound healing and tumor expansion. The broad long term objective of the study is to identify and characterize resident cells in the skin that give rise to tumor-associated stromal cells including endothelial cells. Towards this goal, we propose 3 specific aims. In specific aim 1, we will define stromal cell subsets using a combination of lineage and stem cell markers, determine their numbers and spatial distribution, and confirm their origin in both tumor and in adjacent skin tissue. In specific aim 2, we will isolate stromal cell subsets and examine their lineage relationships based on gene expression patterns. In specific aim 3, we will determine the frequency of stromal cell subsets to form vascular structures in vivo. The identification of resident stromal stem cells will reveal new targets for inhibiting tumor growth, provide a foundation for a more detailed understanding of tumor and adult stem cell biology, and have an important impact on promoting wound healing and tissue engineering. PUBLIC HEALTH RELEVANCE: The identification of resident stromal stem cells will reveal new targets for inhibiting tumor growth, provide a foundation for a more detailed understanding of tumor and adult stem cell biology, and have an important impact on promoting wound healing and tissue engineering.