Stern Mariana C, Benavides Fernando, LaCava Margaret, Conti Claudio J
The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Mol Carcinog. 2002 Sep;35(1):13-20. doi: 10.1002/mc.10067.
Susceptibility to tumor development varies among individuals in the human population. This variability can also be found among different strains of mice, particularly in the mouse skin chemical carcinogenesis model. The genetic mechanisms underlying mouse skin tumor susceptibility are not fully understood. The SENCAR stock has been found to be the most sensitive mice for skin carcinogenesis studies; however, little is known about the genes underlying tumor susceptibility, particularly, those involved in tumor progression. Experiments with the SSIN/Sprd mice, an inbred strain derived from the outbred SENCAR stock, suggested that papilloma development, tumor promotion, and their conversion into squamous cell carcinomas (SCCs), progression, are regulated by different genes. In the highly sensitive SSIN/Sprd mice, papillomas rarely progress to SCC. Using crosses between the outbred SENCAR and the SSIN/Sprd mice, we previously determined that papilloma progression in the SENCAR stock could be controlled by at least one autosomal dominant gene. However, the outbred nature of the SENCAR stock precluded us from extending those findings. More recently, another inbred strain was developed from the outbred SENCAR stock, the SENCARB/Pt. These mice have similar tumor promotion sensitivity to the SSIN/Sprd but in contrast, have high papilloma progression susceptibility, similar to the outbred original stock. In the present study, we generated F(1), F(2), and backcross hybrids between the SSIN/Sprd and SENCARB/Pt mice to determine a possible model for tumor progression susceptibility and to map the putative tumor susceptibility genes. Our tumor data suggests that papilloma progression susceptibility in the SENCAR mouse skin model could be genetically determined by one susceptibility gene. Our preliminary linkage analysis failed to identify one strong susceptibility locus to confirm this but provided some evidence for at least one possible susceptibility locus in mouse chromosome 14.
人群中个体对肿瘤发生的易感性存在差异。这种变异性在不同品系的小鼠中也能发现，尤其是在小鼠皮肤化学致癌模型中。小鼠皮肤肿瘤易感性的遗传机制尚未完全明确。已发现SENCAR种群是皮肤致癌研究中最敏感的小鼠；然而，对于肿瘤易感性的相关基因，尤其是那些参与肿瘤进展的基因，人们了解甚少。对源自远交SENCAR种群的近交系SSIN/Sprd小鼠进行的实验表明，乳头状瘤的发生、肿瘤促进以及它们向鳞状细胞癌（SCC）的转化，即进展，受不同基因调控。在高度敏感的SSIN/Sprd小鼠中，乳头状瘤很少进展为SCC。利用远交SENCAR小鼠与SSIN/Sprd小鼠杂交，我们之前确定SENCAR种群中乳头状瘤的进展可由至少一个常染色体显性基因控制。然而，SENCAR种群的远交特性使我们无法进一步拓展这些发现。最近，又从远交SENCAR种群培育出了另一个近交系SENCARB/Pt。这些小鼠与SSIN/Sprd具有相似的肿瘤促进敏感性，但与之相反，它们具有较高的乳头状瘤进展易感性，类似于远交亲本种群。在本研究中，我们培育了SSIN/Sprd小鼠与SENCARB/Pt小鼠之间的F(1)、F(2)和回交杂种，以确定肿瘤进展易感性的可能模型，并对假定的肿瘤易感性基因进行定位。我们的肿瘤数据表明，SENCAR小鼠皮肤模型中乳头状瘤进展易感性可能由一个易感性基因遗传决定。我们的初步连锁分析未能确定一个强有力的易感性位点来证实这一点，但为小鼠14号染色体上至少一个可能的易感性位点提供了一些证据。
