Contribution of resident stem cells to tumor stroma and vasculature

描述(申请人提供)：癌症干细胞可能构成一种罕见的肿瘤细胞群体，具有自我更新和产生大量转化细胞的能力。尽管癌症干细胞具有潜在的重要性，但它不能单独维持肿瘤组织。包括内皮细胞在内的肿瘤相关间质细胞构成了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，它与干细胞计划紧密结合，在生理和病理过程中都能产生组织。大量研究表明，绝大多数新生血管内皮细胞来源于非造血干细胞，而不是骨髓源性造血干细胞。因此，相当一部分与肿瘤相关的基质细胞可能来自于外周组织中的祖细胞。皮肤是最大的器官，包含许多干细胞，如角质形成细胞干细胞，参与其维护和修复。此外，我们还假设，在伤口愈合和肿瘤扩张过程中，皮肤中的驻留干细胞对血管和间质的作用尚不充分。这项研究广泛的长期目标是鉴定和表征皮肤中的驻留细胞，这些细胞可以产生与肿瘤相关的间质细胞，包括内皮细胞。针对这一目标，我们提出了三个具体目标。在具体目标1中，我们将使用谱系和干细胞标记的组合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来源。在特定的目标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。对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提供基础，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：对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人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.