Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice.
BACKGROUND
Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis.


METHODS
PC-3 cells (5 x 10(5)) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry.


RESULTS
Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96-485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209-1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed.


CONCLUSIONS
Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by decreased angiogenesis and increased apoptosis. The results suggest that bisphosphonates have anti-tumoral and anti-invasive effects on primary prostate cancer.
Tuomela
Johanna M
JM
Institute of Biomedicine, Department of Anatomy, University of Turku, Finland. jomitu@utu.fi
Valta
Maija P
MP
Väänänen
Kalervo
K
Härkönen
Pirkko L
PL
D000230:Adenocarcinoma / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary*; D019386:Alendronate / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013047:Specific Pathogen-Free Organisms; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019386:Alendronate