There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1a (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor a, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r 5 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r 5 20.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell-macrophage interactions augmented macrophagederived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p 5 0.029), but tumoral MCP-1 did not (p 5 0.105). These findings indicate that stromal MCP-1 produced as a result of tumorstromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor-stroma interaction. ' 2009 UICC Key words: macrophage; breast cancer; stroma; monocyte chemoattractant protein-1 (MCP-1); tumor-associated macrophages (TAMs) Tumors consist of both tumor cells and stromal cells surrounded by an extracellular matrix. Recent studies have shown that interactions between tumor and stromal cells create a unique microenvironment which is essential for tumor progression.

Aim : To clarify the influence of hypertension on lower urinary tract symptoms (LUTS) we examined the relationship between blood pressure, LUTS, and the effect of terazosin on LUTS in patients with benign prostatic hyperplasia (BPH). Methods : The subjects were patients who had LUTS and BPH. They were treated with terazosin (1 mg, twice-a-day) for 12 weeks. Calculation of the International Prostate Symptom Score (IPSS), measurement of blood pressure, and uroflowmetry were performed before and after 12 weeks of therapy. Patients were divided into a normotensive (NT) group and a hypertensive (HT) group at the time of first examination. Results : The IPSS for urinary frequency and nocturia in BPH-HT patients ( n = 21; mean age, 71 years) were significantly higher than those in the BPH-NT patients ( n = 21; mean age, 69 years) before the administration of terazosin. The total IPSS the BPH-HT patients was also significantly higher than that of the BPH-NT patients. There were no differences of uroflowmetric parameters between the two groups. After 12 weeks of therapy, systolic and diastolic blood pressure decreased in the BPH-HT patients, but not in the BPH-NT patients. However, the systolic pressure of the BPH-HT patients was still significantly higher than that of the BPH-NT patients. The score for each IPSS parameter decreased in both groups, but the difference of the score between the two groups increased. Conclusion : Hypertension may worsen LUTS and may decrease the improvement of symptoms by terazosin.

Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer.Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells.Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II-induced proliferation of MDA PCa 2b cells.Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121-9. ©2010 AACR.Bone has long been recognized as the most common target organ for prostate cancer metastasis (1, 2). Bone metastasis causes skeletal complications and results in poor prostate cancer outcome in patients (3). Unfortunately, the efficacy of conventional therapies, including androgen deprivation, for the bone metastasis is limited. Despite extensive efforts to develop new therapeutic approach, more efficient treatment of bone metastases from prostate cancer has not been established.Although the precise reason why prostate cancer cells prefer bone tissue is not fully understood, one hypothesis is that the bone is a source of abundant growth factors required for the growth and survival of prostate cancer cells (4). Previously, we established a bone-specific metastasis model of human prostate cancer to investigate the mechanism of bone metastasis from prostate cancer (5). Using this model, in which human adult bones (HAB) were engrafted in mice, we showed previously that the release of growth factors, such as insulin-like growth factors (IGF), arising from bone resorption induced by the tumor cells was important for bone metastasis from prostate cancer (6, 7).IGFs are the most abundant growth factors stored in bone matrix (8). The actions of IGFs are inhibited when they bind to IGF-binding proteins. Prostate cancer cells are known to secrete certa...