Pettan-Brewer Christina, Morton John, Coil Rebecca, Hopkins Heather, Fatemie Sy, Ladiges Warren
Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
Pathobiol Aging Age Relat Dis. 2012;2. doi: 10.3402/pba.v2i0.19182. Epub 2012 Aug 20.
A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×10(5) tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6) and C57BL/6×BALB/c F1 (CB6 F1) mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm(3). The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm(3), respectively (p≤0.001). The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm(3). The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm(3), respectively (p≤0.01). The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm(3) for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm(3), respectively (p≤0.05). The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm(3) for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm(3) (p≤0.01). In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average tumor volumes of 417.62 and 216.34 mm(3) in the 16- and 24-month age groups, respectively (p≤0.005). Histologically, implanted tumors in young mice exhibited characteristics of aggressive, rapidly growing tumor cells including high vascularity, mitosis, and invasiveness compared to tumors in old mice. We contend that the decrease in B16 melanoma tumor growth seen with increasing age in B6 and CB6 F1 mice represents a biological process, which we are calling age-dependent cancer resistance (ADCR). Our data provide a detailed description of conditions necessary to use the model to investigate the mechanisms of ADCR and determine its biological and clinical relevance.
癌症的一个主要风险因素是年龄增长，这表明在老年小鼠中植入同基因肿瘤会生长得更快。然而，各种报告表明，老年小鼠对植入的肿瘤细胞的接受程度不如年轻小鼠。为了确定并描述对B16黑色素瘤的年龄相关反应，我们将5×10⁵个肿瘤细胞皮下植入8、16、24和32月龄的雄性C57BL/6（B6）和C57BL/6×BALB/c F1（CB6 F1）小鼠的腹股沟和腋窝处，或皮内植入侧腹。结果显示，随着年龄增长肿瘤体积减小，这因小鼠遗传背景和植入部位而异。B6品系在8月龄时腹股沟植入部位肿瘤生长旺盛，平均肿瘤体积为1341.25立方毫米。16、24和32月龄组肿瘤生长减少，肿瘤体积分别为563.69、481.02和264.55立方毫米（p≤0.001）。腋窝植入部位对8月龄B6小鼠的接受程度较低，平均肿瘤体积为761.52立方毫米。24和32月龄组肿瘤生长也有类似减少，肿瘤体积分别为440和178.19立方毫米（p≤0.01）。CB6F1品系在8月龄时对肿瘤的接受程度不如B6小鼠，腹股沟和腋窝部位的平均肿瘤体积分别为446.96和426.91立方毫米。24月龄时，腹股沟和腋窝部位的肿瘤生长均减少，平均肿瘤体积分别为271.02和249.12立方毫米（p≤0.05）。在皮内注射B16黑色素瘤细胞的8月龄小鼠中，品系依赖性不明显，B6和CB6 F1的平均肿瘤体积分别为736.82和842.85立方毫米。然而，在32月龄的B6小鼠中观察到品系差异，肿瘤体积平均减少250.83立方毫米（p≤0.01）。相比之下，CB6 F1小鼠的肿瘤生长在更早阶段显著减少，16和24月龄组的平均肿瘤体积分别为417.62和216.34立方毫米（p≤0.005）。组织学上，与老年小鼠的肿瘤相比，年轻小鼠植入的肿瘤表现出侵袭性、快速生长的肿瘤细胞的特征，包括高血管化、有丝分裂和侵袭性。我们认为，B6和CB6 F1小鼠中随着年龄增长B16黑色素瘤肿瘤生长的减少代表了一个生物学过程，我们将其称为年龄依赖性癌症抵抗（ADCR）。我们的数据详细描述了使用该模型研究ADCR机制并确定其生物学和临床相关性所需的条件。
