Angelucci Adriano, Gravina Giovanni Luca, Rucci Nadia, Festuccia Claudio, Muzi Paola, Vicentini Carlo, Teti Anna, Bologna Mauro
Department of Basic and Applied Biology, University of L'Aquila, Medical School and Science and Technology School, Coppito-2, I-67100 L'Aquila, Italy.
Int J Oncol. 2004 Dec;25(6):1713-20.
Prostate cancer is frequently associated with bone metastases, which are in fact the main cause of morbidity and mortality for this tumor. To better investigate this process, animal models of bone and bone marrow metastases need to be developed. However, experimental prostate cancer bone metastases are difficult to be obtained in vivo, and some typical clinical patterns remain irreproducible. In this study, we injected PC3 prostate cancer cells into the left cardiac ventricle of nude mice, thus reproducing the basic biological phenomenon of tumor cell spreading in the arterious blood stream, and compared the outcome with direct injection of cells in the bone marrow cavity of the tibia. Mice were monitored by X-ray analysis. After 40 days, 100% of intratibially-injected and 64% of heart-injected mice revealed osteolytic lesions. The heart injection was then used to select PC3 cell subpopulations by serial inoculation and recovery from bone metastasis. One of the resulting cell populations, obtained by a second round of selection and denominated PCb2, showed a more invasive phenotype compared to parental PC3, both in vitro and in vivo. Although PCb2 cells had a growth rate comparable to that of PC3 cells, they generated a higher number of bone lesions in nude mice and crossed more easily the Matrigel barrier in vitro in the presence of several chemoattractants. This phenomenon was partially due to an increased capacity to adhere to laminin and to release MMP-2 at higher level relative to the original PC3 cells. This study demonstrates that heart injection of prostate cancer cells in nude mice may represent a good experimental model to investigate the pathophysiology of bone and bone marrow metastases in vivo.
前列腺癌常伴有骨转移，事实上这是该肿瘤发病和死亡的主要原因。为了更好地研究这一过程，需要建立骨和骨髓转移的动物模型。然而，实验性前列腺癌骨转移在体内难以获得，一些典型的临床模式仍无法重现。在本研究中，我们将PC3前列腺癌细胞注入裸鼠左心室，从而重现肿瘤细胞在动脉血流中扩散的基本生物学现象，并将结果与直接将细胞注入胫骨骨髓腔进行比较。通过X射线分析对小鼠进行监测。40天后，100%经胫骨内注射的小鼠和64%经心脏注射的小鼠出现溶骨性病变。然后通过连续接种和从骨转移灶中回收，利用心脏注射法筛选PC3细胞亚群。通过第二轮筛选获得的一个细胞群体命名为PCb2，与亲本PC3相比，在体外和体内均表现出更强的侵袭性表型。尽管PCb2细胞的生长速度与PC3细胞相当，但它们在裸鼠中产生更多的骨病变，并且在存在几种趋化因子的情况下，在体外更容易穿过基质胶屏障。这种现象部分归因于相对于原始PC3细胞，其黏附层粘连蛋白的能力增强以及释放更高水平MMP-2的能力增强。本研究表明，向裸鼠心脏注射前列腺癌细胞可能是一种在体内研究骨和骨髓转移病理生理学的良好实验模型。
