ABSTRACT

Lung cancer remains the leading cause of cancer death in the United States. Since most lung cancers occur in aged individuals with chronic lung disorders characterized by inflammation and/or fibrosis, we hypothesized that aging and tissue inflammation/remodeling act in concert to promote lung cancer progression. To test this, we engaged in studies using young and aged C57BL/6 mice in conjunction with bleomycin treatment in a syngeneic model of lung cancer. Wildtype young (3 months) and aged (9 months) C57BL/6 mice were injected with Lewis Lung Carcinoma (LLC) cells at day 14 after injection with phosphate-buffered saline or bleomycin. Untreated aged mice were found to develop more lung metastases than young mice. Bleomycin induced weight loss and lung inflammation/remodeling in both young and aged mice, and it increased the number of lung metastases in aged lungs, but not in young lungs. Since aged lungs show alterations in the expression of fibronectin EDA, we repeated studies in aged WT and aged FN EDA KO mice. In the absence of tissue remodeling/inflammation, WT and FN EDA KO mice developed the same number of metastases when injected with LLC cells. However, the increase in lung metastasis due to bleomycin treatment was abolished in FN EDA KO mice, but only in aged and injured lungs. Together, these studies show increased lung cancer metastasis in aging animals and point to the influence of FN EDA and injury in this process.

摘要

肺癌仍然是美国癌症死亡的主要原因。由于大多数肺癌发生在以炎症和/或纤维化为特征的慢性肺部疾病的老年个体中，我们假设衰老和组织炎症/重塑共同促进肺癌进展。为了测试这一点，我们在肺癌同基因模型中使用年轻和老年 C57BL/6 小鼠结合博来霉素治疗进行了研究。在注射磷酸盐缓冲盐水或博莱霉素后第 14 天，向野生型年轻（3 个月）和老年（9 个月）C57BL/6 小鼠注射路易斯肺癌 (LLC) 细胞。发现未经治疗的老年小鼠比年轻小鼠发生更多的肺转移。博莱霉素在年轻和老年小鼠中诱导体重减轻和肺部炎症/重塑，它增加了老年肺中肺转移的数量，但在年轻肺中没有增加。由于老年肺显示纤连蛋白 EDA 表达的改变，我们在老年 WT 和老年 FN EDA KO 小鼠中重复研究。在没有组织重塑/炎症的情况下，WT 和 FN EDA KO 小鼠在注射 LLC 细胞时发生了相同数量的转移。然而，博来霉素治疗引起的肺转移增加在 FN EDA KO 小鼠中被消除，但仅在衰老和受伤的肺中消失。总之，这些研究表明衰老动物的肺癌转移增加，并指出 FN EDA 和损伤在这一过程中的影响。当注射 LLC 细胞时，WT 和 FN EDA KO 小鼠发生了相同数量的转移。然而，博来霉素治疗引起的肺转移增加在 FN EDA KO 小鼠中被消除，但仅在衰老和受伤的肺中消失。总之，这些研究表明衰老动物的肺癌转移增加，并指出 FN EDA 和损伤在这一过程中的影响。当注射 LLC 细胞时，WT 和 FN EDA KO 小鼠发生了相同数量的转移。然而，博来霉素治疗引起的肺转移增加在 FN EDA KO 小鼠中被消除，但仅在衰老和受伤的肺中消失。总之，这些研究表明衰老动物的肺癌转移增加，并指出 FN EDA 和损伤在这一过程中的影响。