Brakenhielm Ebba, Burton Jeremy B, Johnson Mai, Chavarria Nelson, Morizono Kouki, Chen Irvin, Alitalo Kari, Wu Lily
Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Int J Cancer. 2007 Nov 15;121(10):2153-61. doi: 10.1002/ijc.22900.
Prostate cancer dissemination is difficult to detect in the clinic, and few treatment options exist for patients with advanced-stage disease. Our aim was to investigate the role of tumor lymphangiogenesis during metastasis. Further, we implemented a noninvasive molecular imaging technique to facilitate the assessment of the metastatic process. The metastatic potentials of several human prostate cancer xenograft models, LAPC-4, LAPC-9, PC3 and CWR22Rv-1 were compared. The cells were labeled with luciferase, a bioluminescence imaging reporter gene, to enable optical imaging. After tumor implantation the animals were examined weekly during several months for the appearance of metastases. Metastatic lesions were confirmed by immunohistochemistry. Additionally, the angiogenic and lymphangiogenic profiles of the tumors were characterized. To confirm the role of lymphangiogenesis in mediating metastasis, the low-metastatic LAPC-9 tumor cells were engineered to overexpress VEGF-C, and the development of metastases was evaluated. Our results show CWR22Rv-1 and PC3 tumor cell lines to be more metastatic than LAPC-4, which in turn disseminates more readily than LAPC-9. The difference in metastatic potential correlated with the endogenous production levels of lymphangiogenic growth factor VEGF-C and the presence of tumor lymphatics. In agreement, induced overexpression of VEGF-C in LAPC-9 enhanced tumor lymphangiogenesis leading to the development of metastatic lesions. Taken together, our studies, based on a molecular imaging approach for semiquantitative detection of micrometastases, point to an important role of tumor lymphatics in the metastatic process of human prostate cancer. In particular, VEGF-C seems to play a key role in prostate cancer metastasis.
前列腺癌的扩散在临床上很难检测到，对于晚期疾病患者几乎没有治疗选择。我们的目的是研究肿瘤淋巴管生成在转移过程中的作用。此外，我们采用了一种非侵入性分子成像技术来促进对转移过程的评估。比较了几种人前列腺癌异种移植模型LAPC-4、LAPC-9、PC3和CWR22Rv-1的转移潜能。用荧光素酶（一种生物发光成像报告基因）标记细胞，以实现光学成像。肿瘤植入后，在几个月内每周检查动物是否出现转移。通过免疫组织化学确认转移病灶。此外，还对肿瘤的血管生成和淋巴管生成特征进行了表征。为了证实淋巴管生成在介导转移中的作用，对低转移的LAPC-9肿瘤细胞进行基因工程改造以使其过表达VEGF-C，并评估转移的发展情况。我们的结果表明，CWR22Rv-1和PC3肿瘤细胞系比LAPC-4更具转移性，而LAPC-4又比LAPC-9更容易扩散。转移潜能的差异与淋巴管生成生长因子VEGF-C的内源性产生水平以及肿瘤淋巴管的存在相关。一致的是，LAPC-9中VEGF-C的诱导过表达增强了肿瘤淋巴管生成，导致转移病灶的发展。综上所述，我们基于分子成像方法对微转移进行半定量检测的研究表明，肿瘤淋巴管在人前列腺癌转移过程中起着重要作用。特别是，VEGF-C似乎在前列腺癌转移中起关键作用。
