Endothelial and head & neck cancer stem cell crosstalks and resistance to therapy

内皮和头部

• 批准号: 7663167
• 负责人: Jacques Eduardo Nor
• 金额: $ 22.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663167
• 关键词: Address; Agar; American; Biological Models; Biopsy; Blood Vessels; CD44 gene; Cell Cycle; Cell Fraction; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Coculture Techniques; Conditioned Culture Media; Dermal; Development; Drug Delivery Systems; Endothelial Cells; Engineering; Exposure to; G1 Phase; Gene Silencing; Goals; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hematopoietic stem cells; Human; Implant; In Vitro; Lead; Mediating; Molecular; Mus; Neoplasm Transplantation; Outcome; Pathway interactions; Patients; Pattern; Pericytes; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Physiological; Protocols documentation; Public Health; Recurrence; Research; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; SCID Mice; STAT3 gene; Serum; Signal Transduction; Sorting - Cell Movement; Stem cells; Subfamily lentivirinae; Suspension substance; Suspensions; Testing; Therapeutic; Transplantation; Tumor Angiogenesis; Undifferentiated; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Western Blotting; Work; Xenograft procedure; aldehyde dehydrogenases; base; cancer stem cell; chemotherapy; head and neck cancer patient; immunodeficient mouse model; in vivo; killings; neovascular; nerve stem cell; research study; response; self-renewal; small hairpin RNA; stem cell niche; stemness; subcutaneous; therapy resistant; translational study; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The 5-year survival of patients with advanced head and neck cancer with current therapeutic protocols is very low. Clinical benefit is sometimes observed when anti-angiogenic strategies are combined with standard chemotherapy regimens. However, even in such cases, the survival benefits are modest. The role of anti-angiogenic therapy in the sensitization of head and neck tumors to standard chemotherapy remains unclear. Improvements in the clinical outcome of patients with head and neck cancer are likely to come from a better understanding of mechanisms underlying the overall impact of endothelial cells in tumor pathobiology. Physiological stem cells (e.g. neural stem cells) reside within vascular niches and depend on endothelial cell-derived signaling for their survival. Notably, vascular endothelial growth factor (VEGF) was shown to enhance the survival of hematopoietic stem cells. Tumors, including those of the head and neck, are also populated with stem cells. We have recently shown that neovascular endothelial cells secrete VEGF and that perivascular cells co-express VEGFR1 and stem cell markers (i.e. CD44, ALDH) in human head and neck tumors. The role of stem cells in tumorigenesis is still unclear, but an emerging paradigm proposes that cancer stem cells drive tumor recurrence because they are resistant to conventional chemotherapy. Here, we hypothesize that endothelial cell-secreted VEGF contributes to the stemness and survival of head and neck cancer stem cells, and enhance the resistance of head and neck tumors to chemotherapy with Cisplatin. To test this hypothesis, we propose the following Specific Aims: 1) to evaluate the effect of endothelial cell-initiated VEGF/VEGFR1 signaling on HNCSC stemness and survival; and 2) to study the effect of endothelial cell-initiated VEGF/VEGFR1 signaling on HNCSC survival in xenograft head and neck tumors, and in resistance to chemotherapy with Cisplatin. Head and neck cancer kills 40,000 Americans every year. The majority of these deaths have been associated with the development of evasive resistance to therapy. Very recently, it has been suggested that cancer stem cells are intrinsically involved in resistance to chemotherapy and mediate tumor re-growth. The proposed research utilizes gene silencing strategies for the study of mechanisms regulating molecular crosstalk initiated by endothelial cells that contribute to survival and stemness of head and neck cancer stem cells. In addition, we will perform translational studies to understand the impact of endothelial cells on cancer stem cell-mediated resistance to chemotherapy. These studies will explore new drug targets for overcoming evasive resistance of head and neck tumors to conventional chemotherapy. Project Narrative: The relevance to public health of the proposed research lies in its potential to lead to improvements in the clinical outcomes of head and neck cancer patients. This is critical since the current benefits of therapy are modest for these patients, and their 5-year survival remains very low. The proposed research outlines strategies for obtaining such improvements by :1) studying the role of endothelial cells on the stemness and survival of head and neck cancer stem cells; and by 2) evaluating the role of crosstalk between endothelial cells and head & neck cancer stem cells on response to chemotherapy. The information derived from these studies might lead to the identification of drug targets for the sensitization of head and neck tumors to chemotherapy.

描述（由申请人提供）：采用当前治疗方案的晚期头颈癌患者的 5 年生存率非常低。当抗血管生成策略与标准化疗方案相结合时，有时会观察到临床益处。然而，即使在这种情况下，生存效益也是有限的。抗血管生成治疗在头颈部肿瘤对标准化疗敏感性中的作用仍不清楚。头颈癌患者临床结果的改善可能来自于更好地了解内皮细胞在肿瘤病理学中总体影响的机制。生理干细胞（例如神经干细胞）存在于血管微环境内，并依赖于内皮细胞衍生的信号传导来生存。值得注意的是，血管内皮生长因子（VEGF）被证明可以增强造血干细胞的存活率。肿瘤，包括头部和颈部的肿瘤，也充满了干细胞。我们最近发现，在人类头颈肿瘤中，新生血管内皮细胞分泌 VEGF，血管周围细胞共表达 VEGFR1 和干细胞标志物（即 CD44、ALDH）。干细胞在肿瘤发生中的作用仍不清楚，但一种新兴的范式提出，癌症干细胞会驱动肿瘤复发，因为它们对传统化疗有抵抗力。在这里，我们假设内皮细胞分泌的VEGF有助于头颈癌干细胞的干性和存活，并增强头颈肿瘤对顺铂化疗的抵抗力。为了检验这一假设，我们提出以下具体目标：1）评估内皮细胞启动的 VEGF/VEGFR1 信号传导对 HNCSC 干性和存活的影响； 2) 研究内皮细胞启动的 VEGF/VEGFR1 信号传导对异种移植头颈肿瘤中 HNCSC 存活以及对顺铂化疗耐药的影响。每年有 40,000 名美国人死于头颈癌。这些死亡大多数与逃避治疗产生耐药性有关。最近，有人提出癌症干细胞本质上参与化疗耐药并介导肿瘤再生长。拟议的研究利用基因沉默策略来研究调节由内皮细胞引发的分子串扰的机制，这些机制有助于头颈癌干细胞的存活和干性。此外，我们将进行转化研究，以了解内皮细胞对癌症干细胞介导的化疗耐药性的影响。这些研究将探索新的药物靶点，以克服头颈肿瘤对传统化疗的逃避耐药性。项目叙述：拟议研究与公共健康的相关性在于其有可能改善头颈癌患者的临床结果。这一点至关重要，因为目前治疗对这些患者的益处不大，而且他们的 5 年生存率仍然很低。拟议的研究概述了通过以下方式获得此类改进的策略：1）研究内皮细胞对头颈癌干细胞的干性和存活的作用； 2) 评估内皮细胞和头颈癌干细胞之间的串扰对化疗反应的作用。从这些研究中获得的信息可能有助于确定头颈肿瘤对化疗敏感的药物靶点。