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Modulating metastasis by a lymphangiogenic switch in prostate cancer
Author(s) -
Brakenhielm Ebba,
Burton Jeremy B.,
Johnson Mai,
Chavarria Nelson,
Morizono Kouki,
Chen Irvin,
Alitalo Kari,
Wu Lily
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22900
Subject(s) - lymphangiogenesis , medicine , prostate cancer , metastasis , primary tumor , pathology , cancer , lymphatic system , cancer research , bioluminescence imaging , prostate , biology , cell culture , luciferase , transfection , genetics
Abstract 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. © 2007 Wiley‐Liss, Inc.