Arbeit J M, Riley R R, Huey B, Porter C, Kelloff G, Lubet R, Ward J M, Pinkel D
UCSF Cancer Center, San Francisco, California 94143, USA.
Cancer Res. 1999 Aug 1;59(15):3610-20.
To be informative for chemoprevention, animal models must both closely emulate human disease and possess surrogate endpoint biomarkers that facilitate rapid drug screening. This study elucidated site-specific histopathological and biochemical surrogate endpoint biomarkers of spontaneous epidermal carcinogenesis in K14-HPV16 transgenic mice and demonstrated that the incidence and severity of these markers were decreased by the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO). The cumulative incidence of visible epidermal cancers in 127 untreated transgenic mice was 42% by 52 weeks of age, most frequently affecting the chest as flat lesions in association with chronic ulcers, or in the ear as protuberant masses. Microscopic malignancies were detected in 39% of 32-week-old transgenic mice and were found to emerge from precursor lesions that were of two distinct types: dysplastic sessile ear papillomas and hyperproliferative follicular/interfollicular chest dysplasias. ODC activity and tissue polyamine contents were differentially elevated in ear and chest skin during carcinogenesis, such that there was a marked elevation of both parameters of polyamine metabolism as early as 4 weeks of age in the ear, whereas in the chest, polyamine metabolism was increased significantly only in the late stages of neoplastic progression and in epidermal cancers. Administration of 1.0% DFMO in the drinking water from 4 to 32 weeks of age prevented both visible and microscopic malignancies and significantly decreased the incidence of chest and ear precursor lesions. ODC activity and tissue putrescine content were markedly diminished by DFMO chemoprevention in ear skin, whereas there was a more modest decline of these parameters in chest skin. DFMO treatment of transgenic mice from 28 to 32 weeks of age was associated with an absence of ear cancer and a marked regression of dysplastic papillomas. In contrast, the results in chest skin were complex in that the severity of chest precursors diminished, but their incidence was unchanged, and microscopic cancers were still detectable within these lesions. Collectively, this study highlights the utility of multistage epidermal carcinogenesis in K14-HPV16 transgenic mice both for the study of the biology of, and as a screening tool for, novel drugs and chemopreventive regimens.
为了对化学预防提供信息，动物模型必须既能紧密模拟人类疾病，又能拥有有助于快速药物筛选的替代终点生物标志物。本研究阐明了K14-HPV16转基因小鼠自发性表皮癌发生的位点特异性组织病理学和生化替代终点生物标志物，并证明鸟氨酸脱羧酶（ODC）抑制剂二氟甲基鸟氨酸（DFMO）可降低这些标志物的发生率和严重程度。127只未经治疗的转基因小鼠中，到52周龄时可见表皮癌的累积发生率为42%，最常见于胸部，表现为与慢性溃疡相关的扁平病变，或在耳部表现为突出肿物。在32周龄的转基因小鼠中，39%检测到微观恶性肿瘤，发现其起源于两种不同类型的前驱病变：发育异常的无柄耳部乳头瘤和过度增殖的毛囊/毛囊间胸部发育异常。在致癌过程中，耳部和胸部皮肤的ODC活性和组织多胺含量差异升高，以至于早在4周龄时耳部多胺代谢的两个参数就显著升高，而在胸部，多胺代谢仅在肿瘤进展后期和表皮癌中显著增加。从4周龄到32周龄在饮用水中给予1.0%的DFMO可预防可见和微观恶性肿瘤，并显著降低胸部和耳部前驱病变的发生率。在耳部皮肤中，DFMO化学预防可显著降低ODC活性和组织腐胺含量，而在胸部皮肤中这些参数的下降幅度较小。从28周龄到32周龄对转基因小鼠进行DFMO治疗，可使耳部无癌发生，并使发育异常的乳头瘤显著消退。相比之下，胸部皮肤的结果较为复杂，即胸部前驱病变的严重程度降低，但其发生率不变，并且在这些病变中仍可检测到微观癌症。总体而言，本研究强调了K14-HPV16转基因小鼠多阶段表皮癌发生在研究新型药物和化学预防方案的生物学特性以及作为筛选工具方面的实用性。
