Regulation of Inflammation-Associated Epithelial Cancer Development

摘要： 众所周知，慢性炎症有助于癌症的发展。许多研究都有 证明炎性白细胞通过提供可溶性生长和促进上皮癌 生存因子对启动的细胞和促进组织重塑和血管生成通过合成 因此，肿瘤发生所必需的生理过程，例如， 增强细胞存活、组织重塑和血管生成，是由白细胞和 他们提供了可溶的调解剂。然而，负责引发和/或 促进发展中肿瘤生长的慢性炎症途径的维持不是 很好理解。我们之前曾报道过适应性免疫细胞的挑衅作用 炎症相关上皮癌发展的调节因子。使用HPV16转基因 小鼠鳞状细胞癌模型的发展，我们发现适应性B和T的基因缺失 淋巴细胞导致先天免疫细胞向癌前皮肤的募集减弱。作为一名 结果，组织重塑、血管生成和上皮细胞过度增殖显著 减弱，最终降低癌症发病率。重要的是，B220+CD19+B细胞或 HPV16小鼠血清对T、B淋巴细胞缺陷/HPV16小鼠的免疫修复作用 癌前病变的特征，例如，免疫球蛋白在肿瘤皮肤中的沉积，招募 天然白细胞、血管新生血管的激活和角质形成细胞的过度增殖。一起， 这些数据支持这样的假设，即外周B细胞激活是早期治疗的关键步骤 上皮肿瘤和B细胞衍生的可溶性介质是建立慢性疾病所必需的 促进恶性进展的炎症状态。基于这一假设，总体上 此应用程序的目标是检查B淋巴细胞的特异性靶向或相反，特异性 靶向B淋巴细胞效应通路是抗癌治疗的有效靶点 心理治疗。为了评估这一点，我们建议：1)确定肿瘤进展的参数 B淋巴细胞依赖的HPV16小鼠；2)确定肿瘤参数 HPV16小鼠的进展依赖于FCR；3)定义具有重要功能的髓系细胞 由体液免疫调节的增强致癌作用的类型。项目说明： 我们项目的主要目标是检查B淋巴细胞的特定靶点，或者相反，特定的 靶向B淋巴细胞效应通路是治疗慢性阻塞性肺疾病的可行策略 与上皮癌发展相关的炎症。监管机构的识别 启动或维持慢性炎症所必需的细胞/分子/途径 上皮性肿瘤，将提供有价值的抗癌治疗靶点，用来对抗生长和 实体肿瘤的进展。

ABSTRACT: It is well established that chronic inflammation contributes to cancer development. Many studies have demonstrated that inflammatory leukocytes promote epithelial cancer by providing soluble growth and survival factors to initiated cells and contribute to tissue remodeling and angiogenesis via synthesis of extracellular proteases; thus, physiological processes necessary for tumor development, e.g., enhanced cell survival, tissue remodeling and angiogenesis, are regulated by leukocytes and the soluble mediators they deliver. However, molecular mechanisms responsible for initiation and/or maintenance of chronic inflammatory pathways that potentiate growth of developing neoplasms are not well understood. We have previously reported a provocative role for adaptive immune cells as regulators of inflammation-associated epithelial cancer development. Using the HPV16 transgenic mouse model of squamous carcinoma development, we found that genetic deletion of adaptive B and T lymphocytes resulted in attenuated recruitment of innate immune cells towards premalignant skin. As a consequence, tissue remodeling, angiogenesis and epithelial hyperproliferation were significantly attenuated, culminating in reduced carcinoma incidence. Importantly, transfer of B220+CD19+ B cells or serum from HPV16 mice into T and B lymphocyte-deficient/HPV16 mice resulted in restored characteristics of premalignancy, e.g., immunoglobulin deposition in neoplastic skin, recruitment of innate leukocytes, activation of angiogenic vasculature and keratinocyte hyperproliferation. Together, these data support the hypothesis that peripheral B cell activation is an essential step for early epithelial neoplasia and B cell-derived soluble mediators are necessary for establishing chronic inflammatory states that potentiate malignant progression. Based on this hypothesis, the overall goal of this application is to examine whether specific targeting of B lymphocytes or instead, specific targeting of B lymphocyte effector pathways represent viable therapeutic targets for anti-cancer therapy. To assess this, we propose to: 1) Determine the parameters of neoplastic progression in HPV16 mice that are B lymphocyte-dependent; 2) Determine what parameters of neoplastic progression in HPV16 mice are FcR¿-dependent; 3) Define functionally significant myeloid cell types regulated by humoral immunity that potentiate carcinogenesis. PROJECT NARRATIVE: The major goal of our project is to examine whether specific targeting of B lymphocytes, or instead, specific targeting of B lymphocyte effector pathways represent viable therapeutic strategies for attenuating chronic inflammation associated with epithelial cancer development. Identification of regulatory cells/molecules/pathways essential for either initiating or maintaining chronic inflammation associated with epithelial neoplasms, would provide valuable anti-cancer therapeutic targets with which to combat growth and progression of solid tumors.