Keratinocyte responses to vascular endothelial growth factor in carcinogenesis

致癌过程中角质形成细胞对血管内皮生长因子的反应

• 批准号: 7499079
• 负责人: TRACI A WILGUS
• 金额: $ 28.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499079
• 关键词: Academy; Actinic keratosis; American; Angiogenic Factor; Biological Process; Blood capillaries; Case Study; Chemicals; Chronic; Cicatrix; Cutaneous; Data; Dermatology; Development; Diagnosis; Disease; Endothelial Cells; Epithelial Cells; Excision; Exposure to; Financial cost; Genes; Goals; Growth; Growth Factor; Growth and Development function; Hair; Human; In Vitro; Incidence; Knock-out; Knockout Mice; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Malignant Squamous Cell; Mediator of activation protein; Medicare; Mitogens; Modeling; Mus; Neoplasm Metastasis; Neurons; Numbers; Operative Surgical Procedures; Papilloma; Pathologic Processes; Pathway interactions; Patients; Pericytes; Phase; Physiological; Play; Population; Premalignant; Process; Psoriasis; Role; Sampling; Signal Transduction; Site; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Smooth Muscle Myocytes; Squamous cell carcinoma; Staging; Stromal Cells; Thinking; Time; Ultraviolet Rays; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Wound Healing; angiogenesis; cancer diagnosis; cancer therapy; cancer type; capillary; carcinogenesis; cell type; chemical carcinogenesis; cost; in vivo; insight; keratinocyte; lymph nodes; melanocyte; melanoma; monocyte; mouse model; neutrophil; novel; prevent; receptor; research study; response; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Angiogenesis is an important component of the development, growth, and spread of many types of tumors, including malignancies of the skin. VEGF (vascular endothelial growth factor-A) is a potent pro-angiogenic factor, which has been implicated in a variety of processes in the skin, including tumorigenesis. In the skin, high VEGF levels are associated with enhanced papilloma development, increased squamous cell carcinoma numbers, and a higher incidence of lymph node metastasis. In general, VEGF is described as an endothelial cell-specific growth factor and its ability to promote tumorigenesis has been completely linked to its pro-angiogenic effects. However, evidence that the effects of VEGF may not be restricted to endothelial cells is emerging, as VEGF receptors (VEGFR-1 and VEGFR-2) can be expressed by a subset of non-endothelial cell types. Recently, our laboratory has discovered that one of these receptors, VEGFR-1, is expressed by epidermal keratinocytes. We have also demonstrated a functional role for VEGFR-1 in keratinocyte proliferation in vitro and in vivo during the proliferative phase of cutaneous wound healing. Because excessive proliferation is integral to tumor development, our results suggest that VEGF, through interaction with VEGFR- 1, may influence cutaneous tumorigenesis by signaling directly in keratinocytes. The goal of the proposed studies is to determine whether VEGF can directly stimulate keratinocytes through VEGFR-1, and if this direct keratinocyte stimulation by VEGF is involved in skin carcinogenesis. To carry out these studies we will use novel genetically modified mice, which will allow the temporal deletion of VEGFR-1 specifically in keratinocytes. Mouse models of skin carcinogenesis in addition to human skin cancer samples will be used to carry out the following specific aims: 1) Determine the role of keratinocyte VEGFR-1 in chemical skin carcinogenesis, 2) Evaluate the role of keratinocyte VEGFR-1 in photocarcinogenesis, and 3) Examine VEGFR-1 expression and signaling in human keratinocytes and skin tumors. These studies could potentially reveal a novel biological function for VEGF and could uncover a new, direct mechanism for the involvement of VEGF in the promotion of skin carcinogenesis. The data generated from these experiments will provide new information about the mechanisms involved in skin cancer development, which could be important for treating millions of patients diagnosed with this disease each year. PROJECT NARRATIVE: Non-melanoma skin cancer is the most common type of cancer diagnosed, with over a million new cases reported in the U.S. every year. The studies proposed in this application will examine new pathways involved skin cancer development. The information resulting from these studies could lead to a better understanding about the development and growth of skin tumors, and could also result in the development of better ways to prevent and treat skin cancer.

描述（由申请人提供）：血管生成是多种类型肿瘤（包括皮肤恶性肿瘤）发生、生长和扩散的重要组成部分。 VEGF（血管内皮生长因子-A）是一种有效的促血管生成因子，与皮肤的多种过程有关，包括肿瘤发生。在皮肤中，高 VEGF 水平与乳头状瘤发展增强、鳞状细胞癌数量增加以及淋巴结转移发生率较高有关。一般来说，VEGF 被描述为一种内皮细胞特异性生长因子，其促进肿瘤发生的能力与其促血管生成作用完全相关。然而，越来越多的证据表明 VEGF 的作用可能不仅限于内皮细胞，因为 VEGF 受体（VEGFR-1 和 VEGFR-2）可以由非内皮细胞类型的子集表达。最近，我们实验室发现其中一种受体VEGFR-1是由表皮角质形成细胞表达的。我们还证明了 VEGFR-1 在体外和体内皮肤伤口愈合增殖期角质形成细胞增殖中的功能作用。由于过度增殖是肿瘤发展不可或缺的一部分，因此我们的结果表明 VEGF 通过与 VEGFR-1 相互作用，可能通过直接在角质形成细胞中发出信号来影响皮肤肿瘤发生。拟议研究的目标是确定 VEGF 是否可以通过 VEGFR-1 直接刺激角质形成细胞，以及 VEGF 的这种直接刺激角质形成细胞是否与皮肤癌发生有关。为了进行这些研究，我们将使用新型基因改造小鼠，这将允许角质形成细胞中的 VEGFR-1 暂时缺失。除了人类皮肤癌样本外，还将使用小鼠皮肤癌模型来实现以下具体目标：1）确定角质形成细胞 VEGFR-1 在化学性皮肤癌发生中的作用，2）评估角质形成细胞 VEGFR-1 在光致癌发生中的作用和 3) 检查人类角质形成细胞和皮肤肿瘤中的 VEGFR-1 表达和信号传导。这些研究有可能揭示 VEGF 的新生物学功能，并可能揭示 VEGF 参与促进皮肤癌发生的新的直接机制。这些实验产生的数据将提供有关皮肤癌发展机制的新信息，这对于每年治疗数百万诊断患有这种疾病的患者非常重要。 项目叙述：非黑色素瘤皮肤癌是最常见的癌症类型，美国每年报告的新病例超过一百万。本申请中提出的研究将检查涉及皮肤癌发展的新途径。这些研究产生的信息可以使人们更好地了解皮肤肿瘤的发展和生长，也可以导致开发出更好的方法来预防和治疗皮肤癌。