Regulation of Inflammation-Associated Epithelial Cancer Development

描述(由申请人提供)：众所周知，慢性炎症有助于癌症的发展。许多研究表明，炎性白细胞通过向启动的细胞提供可溶性生长和存活因子促进上皮性癌症，并通过合成细胞外蛋白水解酶促进组织重塑和血管生成；因此，肿瘤发生所必需的生理过程，如增强细胞存活、组织重塑和血管生成，受白细胞及其递送的可溶性介质的调节。然而，启动和/或维持促进肿瘤生长的慢性炎症途径的分子机制还不是很清楚。我们之前已经报道过适应性免疫细胞作为炎症相关上皮癌发展的调节者的挑衅作用。利用HPV16转基因小鼠鳞癌模型，我们发现适应性B和T淋巴细胞的基因缺失导致先天免疫细胞向癌前皮肤的募集减弱。结果，组织重塑、血管生成和上皮细胞过度增殖显著减弱，最终降低了癌症发生率。重要的是，将HPV16小鼠的B220+CD19+B细胞或血清转移到T和B淋巴细胞缺陷/HPV16小鼠体内，可以恢复肿瘤前的特征，如免疫球蛋白在肿瘤皮肤中的沉积，固有白细胞的聚集，血管生成的激活和角质形成细胞的过度增殖。综上所述，这些数据支持这样的假设，即外周B细胞激活是早期上皮肿瘤发生的关键步骤，而B细胞衍生的可溶性介质对于建立促进恶性进展的慢性炎症状态是必要的。基于这一假设，这项应用的总体目标是检查B淋巴细胞的特异性靶向或B淋巴细胞效应通路的特异性靶向是否代表了抗癌治疗的可行靶点。为了评估这一点，我们建议：1)确定B淋巴细胞依赖的HPV16小鼠肿瘤进展的参数；2)确定哪些HPV16小鼠的肿瘤进展参数是FCR？依赖的；3)确定由体液免疫调节的、增强致癌作用的功能显著的髓系细胞类型。公共卫生相关性：我们项目的主要目标是检查特定靶向B淋巴细胞，或者相反，特定靶向B淋巴细胞效应通路是否代表了减轻与上皮性癌症发展相关的慢性炎症的可行治疗策略。识别对启动或维持与上皮性肿瘤相关的慢性炎症至关重要的调节细胞/分子/通路，将为对抗实体肿瘤的生长和进展提供有价值的抗癌治疗靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.