Identifying oral cancer stem cell properties affected by the microenvironment

识别受微环境影响的口腔癌干细胞特性

基本信息

批准号：
9304449
负责人：
Antonio Jimeno
金额：
$ 6.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304449
关键词：
Address Affect Aggressive behavior American Association of Cancer Research Back Behavior Behavioral Biological Models Cancer Model Cell physiology Cells Coculture Techniques Consensus Data Environment Epithelial-Stromal Communication Exhibits Fibroblasts Genes Genetically Engineered Mouse Growth Health Hematopoietic stem cells Human Immune Immune response Immune system Implant Libraries Link Malignant Epithelial Cell Malignant Neoplasms Matrigel Invasion Assay Measures Modeling Molecular Profiling Monitor Mus Neoplasm Metastasis One-Step dentin bonding system Patients Population Primary Neoplasm Process Property Radiation Radiation therapy Radioresistance Recurrence Regulation Resistance Role Serial Passage Signal Transduction Sorting - Cell Movement Stromal Cells Sublingual Region System Testing Time Transplantation Tumor-Derived Xenograft Model base cancer initiation cancer stem cell cell stroma implantation in vivo inhibitor/antagonist knock-down malignant mouth neoplasm migration mouse model mouth squamous cell carcinoma novel radiation resistance reconstitution research study self-renewal small hairpin RNA stem stem cell biology stem cell population therapy resistant tool treatment response tumor tumor heterogeneity tumor initiation tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cancer stem cells (CSCs) from oral squamous cell carcinomas (OSCCs) are expected to have properties of self-renewal, metastasis, and treatment resistance. Current model systems for studying CSCs are largely in immune compromised and species-mismatched stromal environments, which do not capture all CSC properties. We have developed "XactMice" in which human OSCCs are transplanted into mice bearing human hematopoietic stem cells (HSC) that reconstitute human immune cells and other HSC-derived human stroma cells. OSCCs in XactMice exhibited pathological and molecular signatures more similar to primary human OSCCs than OSCCs in immune compromised recipient mice. Additionally, we developed genetically engineered mouse models (GEMMs) with spontaneous OSCCs. Using these complementary models, we will study the influence of the microenvironment on CSC properties, and how this alters treatment resistance. First, we will examine if immune system and species-matched stromal cells affect sizes and behaviors of transplanted CSCs, including cancer initiation, metastasis and resistance to radiation, the main therapy for OSCC. Second, we will combine CSCs in co-culture systems with primary cancer associated fibroblasts (CAFs) or CAFs from XactMice from the same patient, and assess if HSC-derived fibroblasts have the same influence as primary CAFs on CSC self-renewal and invasion, and if a small portion of HSC-derived fibroblasts among mouse fibroblasts is sufficient to contribute to CSC behavioral changes. Finally, based on our preliminary data, we will study if inhibiting TGF? signaling hampers CSC properties of cancer initiation, metastasis and radiotherapy resistance, and identify which TGF? signaling components and targets are involved in CSC regulation. Our efforts to transform human cancer models in which human OSCCs grow in immune competent and species-matched stromal cells provide an ideal platform to study the interaction between CSCs and stroma in OSCC. These experiments will advance understanding of CSC biology, tumor- stroma interactions in human cancer, and the prioritization of novel targeted molecules for inhibiting cancer growth and metastasis.

描述（由申请人提供）：预计口服鳞状细胞癌（OSCC）的癌症干细胞（CSC）具有自我更新，转移和治疗耐药性的特性。当前用于研究CSC的模型系统在很大程度上是在免疫受损和物种不匹配的基质环境中，这些环境并未捕获所有CSC特性。我们已经开发了“ XACTMICE”，其中人类OSCC被移植到带有人造血干细胞（HSC）的小鼠中，这些小鼠重建了人类免疫细胞和其他HSC衍生的人基质细胞。 XACTMICE中的OSCC表现出与免疫受损的受体小鼠中的OSCC相比，与原代人OSCC相似的病理和分子特征。此外，我们开发了具有自发OSCC的基因工程小鼠模型（GEMM）。使用这些互补模型，我们将研究微环境对CSC特性的影响，以及该如何改变治疗抗性。首先，我们将检查免疫系统和物种匹配的基质细胞是否会影响移植CSC的大小和行为，包括癌症的启动，转移和对辐射的耐药性，这是OSCC的主要疗法。其次，我们将与同一患者的XACTMICE相关的原发性癌成纤维细胞（CAF）中的CSC结合CSC，并评估HSC衍生的成纤维细胞是否具有与CSC自我更新和入侵的主要CAF相同的影响，以及是否对HSC的FIBROBLOBLOBLOBLOBLOBLLASTION中的fibroBlobllose则造成了相同的影响。最后，根据我们的初步数据，我们将研究抑制TGF吗？信号传导会阻碍癌症开始，转移和放射疗法耐药性的CSC特性，并确定哪种TGF？ CSC调节涉及信号成分和目标。我们为改变人类OSCC在免疫胜任和物种匹配的基质细胞中生长的人类癌症模型的努力提供了研究CSC与OSCC中基质之间相互作用的理想平台。这些实验将提高人们对CSC生物学，人类癌症中肿瘤的相互作用以及对抑制癌症生长和转移的新靶向分子的优先次序的理解。