Molecular Pathology Research for Cancer Diagnostics and Biomarkers

研究的目的是描述和开发人类疾病的新动物模型，并开发更好地描述模型相关性的方法，解决研究进展的关键障碍。其他目标包括开发用于评估和应用疾病生物标志物的新研究技术。在开发癌症诊断方法和研究资源方面取得了进展，这些研究资源可用于开发和确定人类癌症新模型的特征，并可用于适当开发和利用组织生物库。该研究项目包括开发癌症模型的分子诊断能力，开发用于定量病理学的癌症标本自动形态图像分析方法，以及粘膜黑色素瘤靶向治疗的临床前开发。开发了独特的空间光谱图像分析算法，用于应用自动模式识别形态测量图像分析来量化生物标本组织切片中的组织学肿瘤和非肿瘤组织区域。在开发和验证肺癌和癌症转移的算法方面取得了额外的进展。利用定量光学成像开发和验证了对了解耐药机制重要的新模型。进行了研究，从涉及几种癌症类型的新模型中获得了新的见解。这些研究包括前列腺癌中的碳水化合物代谢、血胎盘屏障的耐药机制、皮肤鳞状细胞癌中的MET信号传导、EGFR驱动的肺癌和顺铂介导的细胞毒性的卵巢癌细胞模型。此外，匹配的原发性和转移性肝癌和结肠癌的特点。黑色素瘤是人类和犬的一种重要恶性肿瘤。与基因工程模型不同，散发性犬黑色素细胞肿瘤与人类疾病有几个共同的特征，这可能使犬成为更相关的临床前模型。犬黑色素瘤很少出现在阳光照射的部位。大多数发生在口腔中，其中一个子集具有模仿人类粘膜黑色素瘤原位组分的上皮内恶性黑色素细胞。犬黑素细胞瘤的范围包括良性病变与痣的一些类似，以及侵袭性原发性黑色素瘤，和广泛转移。越来越多的证据表明，在人类中存在不同的亚型，在体细胞和易感性生殖系遗传改变、细胞起源、流行病学、与紫外线辐射的关系以及从良性肿瘤到恶性肿瘤的进展方面存在差异，也可能存在于犬中。与人皮肤黑色素瘤相比，犬和人粘膜黑色素瘤似乎罕见地具有BRAF、NRAS和c-kit突变，尽管两个物种共享AKT和MAPK信号传导激活。我们的结论是，有显着的重叠，在犬和人类粘膜黑色素瘤的临床和组织病理学特征。这代表了探索犬口腔黑色素瘤作为临床前模型的机会。一个类似的跨学科的方法来比较自然发生的犬脑肿瘤，以告知人类脑癌研究的适用性组织与CCR比较肿瘤学计划和校外调查。

Research is conducted to characterize and develop new animal models of human disease and to develop the means to better characterize a model's relevance, addressing critical barriers to research progress. Additional aims include the development of new research technologies for the evaluation and application of disease biomarkers. Progress was made in developing cancer diagnostics and in research resources useful in developing and characterizing new models of human cancer and for the proper development and utilization of tissue biobanks. This research project included developing capabilities in molecular diagnostics for cancer models, developing methods for automated morphometric image analysis of cancer specimens for quantitative pathology, and preclinical development of targeted therapy for mucosal melanoma. Unique spatial-spectral image analysis algorithms were developed for applying automated pattern recognition morphometric image analysis to quantify histologic tumor and non-tumor tissue areas in biospecimen tissue sections. Additional progress was made in developing and validating algorithms for cancers of lung and cancer metastasis. Contributions to new models important for understanding mechanisms of drug resistance were developed and validated using quantitative optical imaging. Investigations were conducted that led to new insight from novel models involving several cancer types. These included carbohydrate metabolism in prostate cancer, drug resistance mechanisms at the blood placental barrier, MET signaling in cutaneous squamous cancer, EGFR driven lung cancer, and an ovarian cancer cell model of cysplatin-mediated cytotoxicity. In addition matched primary and metastatic liver and colon cancers were characterized. Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant pre-clinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intraepithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a pre-clinical model. An analogous interdisciplinary approach to comparing the suitability of naturally occurring canine brain tumors to inform human brain cancer research was organized with the CCR Comparative Oncology Program and extramural investigators.