Validated Modeling and Culture of Salivary Cancers

描述（由申请人提供）：唾液癌是一组毁灭性的恶性肿瘤，几乎完全通过手术切除或不加放射治疗。发病率低，组织学多样，缺乏分子细节和收集这些肿瘤的基础设施不足，这些都导致了治疗选择的相对缺乏。我们认为，对唾液癌的理解和治疗进展的最大障碍是缺乏或缺乏经过验证的异种移植模型或细胞系进行研究。没有免费的异种移植物或细胞系，机制或临床前研究是不可能的。在这里，我们建议建立多种组织学的人类涎腺癌小鼠异种移植模型。我们移植了多种类型的唾液，包括：腺样囊性、腺癌、多形性低级别腺癌、癌前多形性腺瘤和唾液导管癌。我们还建议使用原发肿瘤或小鼠异种移植肿瘤作为起始材料，从多种组织学类型的涎腺癌中创建细胞系。为了培养细胞系，我们继续优化培养环境，调整肿瘤分离方案、培养基、平板涂层和培养缺氧。通过这些调整，我们已经提高了来自多种唾液癌类型的早期细胞培养的成功率，并且我们目前已经获得了来自腺癌、多形性低级别腺癌和癌前多形性腺瘤的活跃的早期传代细胞。一旦创建了异种移植物和细胞系，将通过形态学（异种移植物）和基因表达（异种移植物和细胞培养）的比较来验证它们。我们拥有从手术切除中收集唾液癌的基础设施，并开发了用于短期培养和小鼠异种移植模型的肿瘤处理专业知识。我们将利用这些资源来创建和验证用于唾液癌的小鼠异种移植模型和细胞系。这些经过验证的细胞系和异种移植肿瘤将对推进对唾液癌的分子理解至关重要，并将对推进治疗至关重要。

DESCRIPTION (provided by applicant): Salivary cancers are a devastating group of malignancies treated almost exclusively by surgical excision with or without radiation. The low incidences, multiple histologies, lack of molecular details and inadequate infrastructure for collecting these tumors have each contributed to the relative paucity of treatment options. We suggest that the largest impediment blocking understanding of salivary cancers and advancement of therapy has been the lack or scarcity of validated xenograft models or cell lines for study. Without freely available xenografts or cell lines mechanistic or pre-clinical studies ar not possible. Here, we propose to create mouse xenograft models of human salivary cancers of multiple histologies. We have xenografted multiple salivary types including: adenoid cystic, adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, carcinoma ex-pleomorphic adenoma, and salivary ductal carcinoma. We also propose to create cell lines from multiple histological types of salivary cancer using primary tumors or murine xenografted tumors as starting material. For development of cell lines, we continue to optimize our culture environment with adjustment of tumor dissociation protocols, media, plate coatings, and culture hypoxia. By making these adjustments, we have increased our success of early cell culture derived from multiple salivary cancer types, and we currently have active early passages of cells derived from adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, and carcinoma ex-pleomorphic adenoma. Once xenografts and cell lines are created, they will be validated by comparison of morphology (xenografts) and gene expression (xenografts and cell cultures). We have the infrastructure for collection of salivary cancers from surgical resections and have developed expertise in processing of the tumors for short-term culture and murine xenograft modeling. We will leverage these resources to create and validate murine xenograft models and cell lines for salivary cancers. These validated cell lines and xenografted tumors will be critical to advance molecular understanding of salivary cancers and will be needed for advancement of therapy.