Jadeski L C, Hum K O, Chakraborty C, Lala P K
Department of Anatomy and Cell Biology, The University of Western Ontario, London, Canada.
Int J Cancer. 2000 Apr 1;86(1):30-9. doi: 10.1002/(sici)1097-0215(20000401)86:1<30::aid-ijc5>3.0.co;2-i.
The contributory role of nitric oxide (NO) on tumour growth and metastasis was evaluated in a murine mammary tumour model. NO synthase (NOS) protein expression levels were examined in spontaneously arising C3H/HeJ mammary adenocarcinomas and respective lung metastases. In addition, 2 clonal derivatives of a single spontaneous tumour differing in metastatic phenotype (C3L5 and C10; highly and weakly metastatic, respectively) were utilised to investigate (i) the relationship between NOS expression levels and the biological behaviour of tumour cells (e.g., in vitro migratory and invasive capacities, in vivo tumour growth rate and metastatic and angiogenic capacities) and (ii) whether tumour-derived NO stimulated the invasive, migratory and angiogenic capacities of tumour cells. A heterogeneous pattern of endothelial NOS (eNOS) expression was observed in tumour cells in spontaneous primary tumours, and eNOS expression was higher in undifferentiated relative to differentiated tumour zones. However, tumour cells in lung metastatic sites were always strongly eNOS-positive, suggesting that eNOS expression facilitated metastasis. Findings using clonal derivatives supported this notion; s.c. primary tumour growth rate, efficiency of spontaneous metastasis and eNOS expression were higher for C3L5 relative to C10 cell lines. Nevertheless, lung metastases derived from both tumour cell lines were always strongly and homogeneously eNOS-positive. C3L5 cells were more invasive than C10 cells in vitro, but the migratory capacities of the cell lines did not differ. However, migration and invasiveness of both cell lines were inhibited with L-NAME and restored with excess L-arginine. Tumour-associated angiogenesis, measured in Matrigel implants inclusive of tumour cells, was higher for C3L5 relative to C10 cells, and C3L5-induced angiogenesis was reduced with chronic L-NAME treatment of host animals. These findings suggest that tumour-derived eNOS promoted tumour growth and metastasis by multiple mechanisms: stimulation of tumour cell migration, invasiveness and angiogenesis.
在小鼠乳腺肿瘤模型中评估了一氧化氮（NO）对肿瘤生长和转移的作用。检测了自发产生的C3H/HeJ乳腺腺癌及其相应肺转移灶中一氧化氮合酶（NOS）蛋白表达水平。此外，利用一个具有不同转移表型的单一自发肿瘤的2个克隆衍生物（C3L5和C10；分别为高转移性和低转移性）来研究：（i）NOS表达水平与肿瘤细胞生物学行为之间的关系（例如，体外迁移和侵袭能力、体内肿瘤生长速率以及转移和血管生成能力）；（ii）肿瘤源性NO是否刺激肿瘤细胞的侵袭、迁移和血管生成能力。在自发原发性肿瘤的肿瘤细胞中观察到内皮型NOS（eNOS）表达的异质性模式，并且未分化肿瘤区域相对于分化肿瘤区域的eNOS表达更高。然而，肺转移部位的肿瘤细胞总是强烈eNOS阳性，表明eNOS表达促进了转移。使用克隆衍生物的研究结果支持了这一观点；相对于C10细胞系，C3L5的皮下原发性肿瘤生长速率、自发转移效率和eNOS表达更高。然而，源自这两种肿瘤细胞系的肺转移灶总是强烈且均匀地eNOS阳性。C3L5细胞在体外比C10细胞更具侵袭性，但这两种细胞系的迁移能力没有差异。然而，两种细胞系的迁移和侵袭能力均被L-NAME抑制，并通过过量的L-精氨酸恢复。在包含肿瘤细胞的基质胶植入物中测量的肿瘤相关血管生成，相对于C10细胞，C3L5更高，并且通过对宿主动物进行慢性L-NAME处理可降低C3L5诱导的血管生成。这些发现表明，肿瘤源性eNOS通过多种机制促进肿瘤生长和转移：刺激肿瘤细胞迁移、侵袭和血管生成。
