Modulating metastasis by a lymphangiogenic switch in prostate cancer

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.

Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

“…Histology was performed, processed, and quantified as previously described. 19 The samples were analyzed using an Olympus BX41 fluorescent microscope fitted with a Q-Imaging QICAM FAST 1394 camera. Images were captured at 4ϫ, 10ϫ, or 20ϫ magnification using QCapture Pro Version 5.1 (Media Cybernetics), quantified using ImageJ Version 1.34s (NIH), and processed using Adobe Photoshop CS.…”

Molecular Imaging of Metastatic Potential

“…All are preclinical. Brakenhielm et al developed a new metastatic model for prostate cancer in which tumor cell lines not normally metastatic were transfected with VEGF-C, which promotes lymphangiogenesis (189). Turning on that ''lymphangiogenic switch'' could be visualized clearly with optical imaging because the cells were also transfected with fLuc as the reporter gene (Fig.…”

Advances in the research on lymphangiogenesis in carcinoma tissues (Review)

“…Clinical trials on human tumors indicated that the expression of VEGF-C or VEGF-D is associated with lymph node metastasis and the poor prognosis of patients with cancer (16). using relevant animal models, it was confirmed that VEGF-C or VEGF-D plays an important role in the regulation of tumor lymphangiogenesis and lymph node metastasis in that the overexpression of VEGF-C was accompanied by intra-and/or peri-LVD and lymphatic metastasis (17). However, Karkkainen et al (18) reported that Vegfc -/-mice cannot generate lymphatic vessels via budding, leading to the dysplasia of lymphatic vessels in tissues and prenatal death from excessive fluid accumulation in tissues.…”

“…Currently, the VEGF-C/VEGF-D/ VEGFR-3 signaling pathways are believed to be the most important mechanism underlying tumor lymphangiogenesis (16)(17)(18)(19)(20)(21)(22).…”