(PQC2) Optical Hallmarks of Aggressive Clones Within Oral Field Cancerization

描述（申请人提供）：口腔癌是全球第六大常见癌症。尽管口腔很容易进行筛查，但口腔癌是所有癌症中5年生存率最低的癌症之一。口腔癌被认为是由恶性肿瘤引起的，通常是对烟草和酒精暴露的反应，粘膜表面的广泛区域发生亚临床癌变。口腔癌预后差的主要原因是：(1)大多数患者诊断较晚，因为使患者处于肿瘤风险的分子变化通常不会引起临床可见的病变；(2)很大一部分接受口腔癌治疗的患者会发展为后续癌症，因为野区癌变在治疗后持续存在，临床不可见。口腔癌的发生和发展最终是一个分子过程，反映了危险区域内一系列复杂的遗传变化。最终，引发肿瘤的干细胞在危险的粘膜场内产生具有攻击性的克隆，导致恶性进展。虽然在了解与口腔癌进展相关的分子改变方面取得了很大进展，但这项研究尚未导致早期检测的改进，主要是因为分子分析方法成本高昂，并且只能通过侵入性活检获得的组织进行。越来越多的证据表明，关键的分子改变导致表型改变，可以在临床护理点测量。本课题组等近期研究表明，与目测检查相比，多模态光学成像可以通过组织荧光和核形态学的变化来识别高级别口腔癌前和早期癌症，其敏感性和特异性显著提高；此外，光学特性的变化与肿瘤进展相关的分子标记密切相关。本提案的目的是验证多模态光学成像提高早期检测的能力，并确定风险相关光学标记物（rrom）是否可用于预测恶性进展的可能性。我们将对口腔病变患者进行纵向研究，使用尖端的自体荧光和带有自动诊断算法的显微内窥镜技术。在口腔癌动物模型中，我们将结合光学成像和新型组织制备技术，使组织具有光学透明性和大分子渗透性，以评估口腔癌发生和进展过程中分子改变与表型变化的时空相关性。根据这些数据，我们建议开发和验证与rrom恶性转化相关的预测模型。

DESCRIPTION (provided by applicant): Oral cancer is the 6th most common cancer worldwide. Despite the easy accessibility of the oral cavity for screening, oral cancer has one of the lowest 5-year survival rates of all cancers. Oral cancer is thought to arise as a result of fied cancerization, where, often in response to tobacco and alcohol exposure, wide areas of the mucosal surface develop subclinical carcinogenetic changes. The poor outcomes of oral cancer arise primarily because: (1) most patients are diagnosed at a late stage since the molecular changes that put patients at risk of neoplasia often do not give rise to clinically visible lesions and (2) a large fraction of patients treated for oral cancer develop subsequent cancers because areas of field cancerization persist following treatment and are not clinically visible. The development and progression of oral cancer is ultimately a molecular process, reflecting a complex succession of genetic changes within the field-at-risk. Ultimately tumor-initiating stem cells give rise to aggressive clones within a mucosal field-at-risk, resulting in malignant progression. While much progress has been made to understand the molecular alterations associated with oral cancer progression, this research has not yet led to improvements in early detection mainly because molecular analysis methods are costly and can only be carried out with tissues obtained from invasive biopsies. There is increasing evidence to suggest that key molecular alterations result in phenotypic changes that can be measured clinically at the point-of-care. Recent studies by our group and others suggest that multi-modal optical imaging can image changes in tissue fluorescence and nuclear morphometry to identify high grade oral precancer and early cancer with significantly improved sensitivity and specificity compared to visual examination; moreover, changes in optical properties correlate strongly with molecular markers associated with neoplastic progression. The goal of this proposal is to validate the ability of multimodal optical imaging to improve early detection and to determine whether risk-related optical markers (RROMs) can be used to predict the likelihood of malignant progression. We will perform longitudinal studies in patients with oral lesions using cutting edge autofluorescence and microendoscopy technology with automated diagnostic algorithms. In an animal model of oral cancer, we will combine optical imaging and novel tissue preparation techniques, which render tissue optically transparent and macromolecular permeable, to assess the temporal and spatial correlations of molecular alterations to phenotypic changes during development and progression of oral cancer. With this data, we propose to develop and validate predictive models relating RROMs to malignant transformation.