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发展。 许多研究已经证明，炎性白细胞通过向起始细胞提供可溶性生长和存活因子来促进上皮癌，并且通过合成细胞外蛋白酶来促进组织重塑和血管生成;因此，肿瘤发展所必需的生理过程，例如，增强的细胞存活、组织重塑和血管生成由白细胞和它们递送的可溶性介质调节。 然而，负责启动和/或维持慢性炎症途径，加强发展中肿瘤的生长的分子机制还没有得到很好的理解。 我们以前曾报道过适应性免疫细胞作为炎症相关上皮癌发展的调节因子的刺激作用。 使用鳞状细胞癌发展的HPV 16转基因小鼠模型，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。 因此，组织重塑，血管生成和上皮细胞过度增殖显着减弱，最终降低癌的发病率。 重要的是，将来自HPV 16小鼠的B220+ CD 19 + B细胞或血清转移到T和B淋巴细胞缺陷/HPV 16小鼠中导致癌前病变特征的恢复，例如，肿瘤皮肤中免疫球蛋白沉积、先天性白细胞的募集、血管生成脉管系统的激活和角质形成细胞过度增殖。 总之，这些数据支持外周B细胞活化是早期上皮瘤形成的必要步骤，并且B细胞衍生的可溶性介质是建立慢性炎症状态所必需的，所述慢性炎症状态增强恶性进展。 基于这一假设，本申请的总体目标是检查特异性靶向B淋巴细胞或替代地特异性靶向B淋巴细胞效应子途径是否代表抗癌疗法的可行治疗靶标。 为了评估这一点，我们建议：1）确定HPV 16小鼠肿瘤进展的参数，这些参数是B淋巴细胞依赖性的; 2）确定HPV 16小鼠肿瘤进展的哪些参数是FcR？-依赖性; 3）定义由增强致癌作用的体液免疫调节的功能显著的髓样细胞类型。 公共卫生相关性：我们项目的主要目标是研究特异性靶向B淋巴细胞，或相反，特异性靶向B淋巴细胞效应通路是否代表了减轻与上皮癌发展相关的慢性炎症的可行治疗策略。 鉴定对于启动或维持与上皮肿瘤相关的慢性炎症至关重要的调节细胞/分子/途径将提供有价值的抗癌治疗靶点，以对抗实体瘤的生长和进展。

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.