Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis.

BACKGROUND: The metastasis of prostate cancer to bone is associated with a substantial increase in bone matrix turnover. Matrix metalloproteinases (MMPs) play roles in both normal bone remodeling and invasion and metastasis of prostate cancer. This study was designed to determine the role of MMP activity in prostate cancer that has metastasized to bone. METHODS: Single human fetal bone fragments were implanted subcutaneously in immunodeficient mice. Four weeks later, PC3 human prostate cancer cells were injected directly into some of the implants, and daily treatment was begun with batimastat (a broad-spectrum MMP inhibitor). There were six mice (i.e., six implants) in each of four experimental arms: bone alone with and without batimastat and bone injected with PC3 cells with and without batimastat. Bone implants were harvested after 14 days of treatment and analyzed for MMP expression, bone histomorphometry, osteoclast counts, blood vessel density, and tumor cell proliferation and apoptosis. Complementary data were obtained from bone biopsy samples from patients and a bone organ coculture system. All statistical tests were two-sided. RESULTS: MMPs were detected in tumor and stromal cells of clinical specimens and experimental bone implants. In vivo, MMP inhibition reduced the number of osteoclasts per millimeter in PC3-injected implants-from 8.2 (95% confidence interval [CI] = 7.9 to 8.5) to 3.0 (95% CI = 2.3 to 3.7) (P =.006). In addition, it prevented degradation of marrow trabeculae within the bone implants (cross-sectional area of implant occupied by mineralized trabeculae: untreated implant = 29.1% [95% CI = 27.1% to 31.1%], PC3-injected implant = 14.0% [95% CI = 10.9% to 17.1%] [P =.005 versus untreated], and batimastat-treated PC3-injected implant = 27.2% [95% CI = 22.4% to 32.0%] [P =.03 versus PC3 injected alone]). MMP inhibition reduced proliferating tumor cells from 20.8% (95% CI = 19.9% to 21.7%) to 7.4% (95% CI = 5.2% to 9.6%) (P =.006), without affecting angiogenesis or apoptosis. In vitro, MMP inhibition had no toxic effect on PC3 cells but prevented calcium release from bone fragments cocultured with PC3 cells. CONCLUSIONS: MMP activity appears to play an important role in bone matrix turnover when prostate cancer cells are present in bone. Bone matrix turnover and metastatic tumor growth appear to be involved in a mutually supportive cycle that is disrupted by MMP inhibition.     

Osteoclast-mediated osteolysis in bone metastasis from renal cell carcinoma

Osteolytic characteristics of bone metastasis from renal cell carcinoma were morphologically and biochemically investigated. First, undecalcified ground sections of bone metastases were made from four patients with renal cell carcinoma. Second, renal cell carcinoma cell line (RCC-K1) was established from one of the four patients, and its effect on bone resorption in vitro was examined. Marked proliferation and activation of osteoclasts around the tumor cells was histologically demonstrated. Conditioned medium from the RCC-K1 cells contained potent bone-resorbing activity in vitro. The activity was reduced to basal level by calcitonin, but was not blocked by indomethacin. The activity was lost after dialysis (MW cutoff 3500), while it was retained after 2 weeks of storage. Levels of prostaglandin E2 and 1,25-dihydroxyvitamin D of the RCC-K1-conditioned medium were insufficient to cause bone resorption in vitro. The conditioned medium did not stimulate cAMP accumulation in rat osteoblastic cells. These results suggest that renal cell carcinoma causes bone destruction through the stimulation of osteoclasts by locally secreting an unknown humoral factor or factors.     

Hepatocellular carcinoma with bone metastasis

The autopsy of hepatocellular carcinoma at Hines VA Hospital was reviewed for a 33-year period, between 1954 and 1986. The neoplasm is uncommon and bone involvement was observed in 7.3% or in ten of 137 cases. A clinical presentation of osseous metastasis in hepatocellular carcinoma is rare. A brief literature review is also included.     

Lung cancer with bone metastasis

Lung cancer is one of the most common solid tumors to develop metastases to bone. The prognosis of patients with metastatic lung cancer to bones is short,usually less than 6 months. The treatment requires a multidisciplinary approach that addresses radiotherapy, surgery, chemotherapy, and medical therapy with analgesics and bisphosphonates. Radiotherapy for metastatic bone tumor is a mainstay to relieve pain and control the localized disease. Doses in the range of 20 Gy in 5 fractions, 30 Gy in 10 fractions are acceptable in most circumstances. Prophylactic fixation for long bone fractures is recommended in cases where 30 to 50% of the cortex has been destroyed, pain is present after radiotherapy, or life expectancy is more than 3 months. Systemic chemotherapy has been proved to prolong survival of patients with metastatic non-small-cell lung cancer (NSCLC) as well as extensive small cell lung cancer (SCLC). Combination chemotherapy of platinum and a new drug is recommended in NSCLC patients with good performance status (PS). Gefitinib in upfront or second-line treatment is an optional therapy in adenocarcinoma patients without a history of smoking. Cisplatin combined with etoposide or irinotecan is a standard therapy in SCLC patients with PS 0 or 1. Carboplatin and etoposide is a treatment of choice in SCLC patients with PS 2 or 3. Medical management of cancer pain requires nonsteroidal anti-inflammatory drugs and opioids. Cancer pain that necessitates more than 120 mg of oral morphine is morphine-resistant pain and requires some adjuvant drugs such as corticosteroids, ketamine,anticonvulsants, or local anesthetics. The third generation bisphosphonate zoledronate has been demonstrated to improve cancer pain and to prevent skeletal morbidity in lung cancer patients with metastatic bone disease.     

分析吉非替尼有效的非小细胞肺癌患者骨转移对其生存期的影响及骨转移患者的预后因素

目的：研究吉非替尼有效的非小细胞肺癌患者,骨转移是否影响其生存期,并分析骨转移患者的预后因素。方法比较骨转移和无骨转移患者总生存、无进展生存、1年、2年及3年生存率,并分析影响骨转移患者预后的因素。结果无骨转移组44例,骨转移组32例。无骨转移组与有骨转移组总生存期（19．000±3．317月 vs．26．000±2．121月,P＝0．625）和无进展生存期（14．000±1．843月 vs．16．000±1．411月,P＝0．328）无统计学差异。前组患者1年生存率63．6％低于后者96．9％,2年和3年生存率分别为（34．1％vs．56．3％,P＝0．054）和（18．2％vs．18．4％,P＝0．950）,无统计学差异。对骨转移组进行单因素分析显示年龄＞60岁及有肺内进展者预后更差,多因素分析显示影响骨转移患者生存的有效因素为有肺内进展,而性别、病理、吸烟指数、是否合并脑转移、骨相关事件及是否应用放疗、双膦酸盐与骨转移患者中位生存时间均无明显相关性。结论吉非替尼治疗有效的非小细胞肺癌患者,骨转移可能不是影响其生存期的主要因素,肺内进展有可能是非小细胞肺癌骨转移者的主要死因,不能将骨转移作为停用吉非替尼的指征。     

细胞粘附分子在肿瘤骨转移中的作用

骨转移是恶性肿瘤最常见的并发症之一.细胞粘附分子主要包括钙粘附素家族、整合素家族、选择素家族、免疫球蛋白超家族和透明质酸粘素(如CD44)等五类,通过同质型粘附和异质型粘附,在肿瘤骨转移中发挥作用.在治疗和预防肿瘤骨转移中,针对CAMs介导的抗粘附治疗将会是一种新的治疗方法.     

Surgical treatment of bone metastasis in advanced renal cell carcinoma

Operative treatments for bone metastases were performed in 7 patients with an advanced renal cell carcinoma. Spinal instrumentation using a Harrington's rod and Luque's wire was the method employed in 4 cases as the initial treatment. In one other case, an anterior fusion by an autologus bone transplantation was used, followed by a posterior fusion. In the 2 remaining cases an endoprosthetic replacement for a metastasis in the right femur and a transplantation of a Kotz's knee joint was done for a metastasis in the left tibia, respectively. In 5 patients with vertebral column lesions, the stabilization of spinal instability was effected by the spinal instrumentation. Three patients with vertebral metastases recovered sufficiently to walk by themselves. This beneficial result was invaluable from the viewpoints of physiotherapy and nursing care.     

Active chemotherapy for bone metastasis in sarcomatoid renal cell carcinoma

 Sarcomatoid renal cell carcinoma (SRCC) is associated with an aggressive course, high incidence of bone metastasis, and an extremely poor prognosis. There are a few case reports concerning the effectiveness of chemotherapy on metastasis in SRCC. To our knowledge, however, there are no reports describing its effectiveness on bone metastasis. We report a 22-year-old woman with an 8-cm × 7-cm left renal mass. Left nephrectomy was done. The pathological diagnosis was SRCC, INF-β, pT3aN2. Although, she received continuous infusion of interferon α-2a (INFα-2a) and interleukin-2 (IL-2) as adjuvant therapy, liver metastasis appeared 2 months later. Resection of the liver metastasis was done. After resection of the metastasis, multiple bone metastases appeared, in both humeri, the left chest wall, the left fourth rib, and the left iliac bone. The patient was treated with gemcitabine, 1000 mg/m² (days 1, 8), docetaxel 80 mg/m² (day 1), and carboplatin 300 mg/m² (day 1). A computed tomography (CT) scan after the first cycle revealed that the multiple osteolytic bone tumors had significantly decreased in size. Her ability of daily life (ADL) improved and this continued for almost 2 months. A second course of chemotherapy, with gemcitabine and IL-2 was given, but it was ineffective, and the patient died approximately 16 months after the initial diagnosis of SRCC. Combination chemotherapy with gemcitabine, docetaxel, and carboplatin was effective for the bone metastasis of SRCC. Received: August 21, 2002 / Accepted: December 10, 2002 Correspondence to:S. Hoshi     

Radiotherapy combined with zoledronate can reduce skeletal-related events in renal cell carcinoma patients with bone metastasis

Background

Skeletal-related events (SRE) are common in patients with renal cell carcinoma (RCC) that includes bone metastasis. The purpose of this study was to clarify the effectiveness of zoledronate with and without sunitinib, combined with radiotherapy, for the treatment of bone metastasis from RCC.

Methods

We retrospectively analyzed 62 RCC patients with bone metastasis, who had been treated with radiotherapy at our institution. We divided the study cohort into two groups: patients treated with radiotherapy alone (RT; n?=?27) and those treated with radiotherapy combined with zoledronate (RT?+?Z; n?=?35). We investigated the overall survival and post-irradiation (PI)-SRE-free rate for each group, as well as the effect of sunitinib in the RT?+?Z treatment group. In addition, we determined treatment effectiveness by imaging assessments and relative response rates.

Results

There was no significant difference in the survival rates between the RT and RT?+?Z treatment groups (p?=?0.11). However, the PI-SRE-free rate in the RT?+?Z group was significantly higher than that in the RT group (p?=?0.02). The PI-SRE-free rate was significantly higher in patients who were treated with sunitinib after radiotherapy than in those who were treated without sunitinib (p?=?0.03). However, there was no significant difference in the relative response rates, as assessed by imaging, in each group.

Conclusion

Radiotherapy combined with zoledronate is an effective treatment for RCC with bone metastasis to prevent PI-SRE. Sunitinib may reduce PI-SRE if used after radiotherapy and combined with zoledronate.

     

非小细胞肺癌骨转移化疗后的骨髓抑制分析

目的：观察晚期非小细胞肺癌骨转移患者化疗后的骨髓抑制程度.方法：将247例晚期非小细胞肺癌患者分为两组,研究组为伴骨转移的患者132例,对照组为无骨转移的患者115例,化疗1周期,进行骨髓抑制和其他不良反应的比较.结果：研究组中化疗后Ⅲ-Ⅳ度白细胞、血小板、红细胞下降的患者比例分别是28.8％、31.1％和20.5％,对照组为15.7％、14.8％和13.0％,差异有统计学意义（P＜0.05）.研究组出现骨髓抑制最严重的平均时间为9天,对照组12天,差异有统计学意义（P＜0.05）.Ⅲ-Ⅳ度恶心、呕吐和流感样症状恶心、呕吐研究组为31.8％、8.3％,对照组为19.1％、1.7％,差异有统计学意义（P＜0.05）.结论：晚期非小细胞肺癌骨转移化疗后更易发生严重的骨髓抑制,且时间提前;恶心、呕吐及流感样症状程度较严重,应注意化疗剂量的调整.     

Nasopharyngeal carcinoma with bone marrow metastasis

Five of 23 patients with recurrent nasopharyngeal carcinoma (NPC) were diagnosed to have bone marrow metastasis. They all had advanced local-regional disease, and were treated with neoadjuvant chemotherapy and definitive radiotherapy after the initial diagnosis. Bone marrow metastasis developed 4-24 months later. The clinical features were anemia (5 of 5), leukopenia (3 of 5), thrombocytopenia (4 of 5), sepsis (3 of 5), tenderness of the sternum (3 of 5), and fever (4 of 5). Patients frequently had elevation of serum lactic dehydrogenase (LDH), alkaline phosphatase (ALK-P), and IgG and IgA antibody titers to Epstein-Barr viral capsid antigen when bone marrow involvement was diagnosed. However, clinical manifestations and laboratory tests were not specific. It is important that three patients had normal bone scans. All five patients had a rapid downhill course; four patients died within 23 days, and the fifth 3 months after the diagnosis of bone marrow metastasis. We concluded that bone marrow was a common metastatic site in NPC patients. Bone marrow metastasis adversely affected patients' survival and required a high index of suspicion for diagnosis. We suggested that bone marrow biopsy should be considered as a routine staging procedure in NPC patients and indicated especially when patients presented with abnormal blood counts, sepsis, bone pain, or tenderness of the sternum. It may be positive in the face of a normal bone scan.     

Hepatocellular carcinoma presenting with bone metastasis

Bone metastasis is an unusual complication of hepatocellular carcinoma. We report here 2 cases of patients with bone metastases of hepatocellular carcinoma at presentation. Patient No. 1 with liver cirrhosis and hepatocellular carcinoma was admitted with a bone metastasis in the rib. The patient was treated with hepatic arterial chemotherapy and rib resection. Patient No.2 was known to have an asymptomatic liver mass of uncertain histology for a year when he presented with back pain. Because of signs of spinal compression, laminectomy was performed, and the diagnosis of metastatic hepatocellular carcinoma was established. The presence of bone metastases in hepatocellular carcinoma at presentation is extremely rare. More frequently, bone lesions are observed after successful treatment of the primary liver tumor. Both surgery and radiotherapy are used as palliative treatment in bone metastases of hepatocellular carcinoma. The treatment of hepatocellular carcinoma presenting with bone metastasis by bone resection and intraarterial chemotherapy seems to be of limited impact on patient survival because of dissemination of micrometastases in other organs and the frequent presence of other comorbid conditions. However, effective palliation using this multimodality approach is feasible. Hepatocellular carcinoma should be considered in the differential diagnosis of bone metastases.     

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan–Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.     

Evaluation of bone metabolic markers in breast cancer with bone metastasis

PURPOSE: In the present study, four bone metabolic markers were examined to clarify them meaning and clinical value in the detection of bone metastasis (BM) from breast cancer. METHODS: we examined serum carboxyterminal telopeptide of type I collagen (ICTP), tartrate resistant acid phosphatase (TRACP), total alkaline phosphatase (ALP) and urinary type I collagen cross-linked N-telopeptides (NTx) as potential markers. These bone markers were evaluated simultaneously in 156 breast cancer patients; 114 patients without metastasis (group A), 23 patients with BM (group B) and 19 patients with metastasis at sites other than bone (group C). RESULTS: The mean values of ICTP and TRACP in group B were significantly greater than those in group A. Group B consisted of the patients with varying degrees of BM and variation in their treatments. The patients in group B were divided into BM (+) and BM (++) according to hot spots in bone scan. ICTP and TRACP were elevated in BM (++) patients compared to BM (+) patients (p<0.05). The values of ICTP and TRACP of the twelve patients without treatment in group B were significantly higher than those in group A. In the treated patients of group B, the mean values of ICTP and TRACP were lower in responders and cases of stable disease than those with progression. NTx and ALP were inferior to ICTP and TRACP for clinical evaluation of BM. CONCLUSIONS: We confirmed that ICTP and TRACP might be useful markers for screening and monitoring BM in breast cancer.     

Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib

BackgroundThe aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib.Patients and methodsWe reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST).ResultsTwo hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P < 0.0001) and 19.5 versus 38.5 months (P < 0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P < 0.0001) and OS (P = 0.001).ConclusionThe presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.     

GPNMB overexpression is associated with extensive bone metastasis and poor prognosis in renal cell carcinoma

Glycoprotein non-metastatic protein B (GPNMB) promotes bone metastasis (BM) in various types of cancer. However, GPNMB expression and its function in patients with renal cell carcinoma (RCC) and BM is still unknown. Therefore, the clinical significance of GPNMB and its biological function in RCC with BM was investigated in the present study. A total of 31 patients with RCC and BM were retrospectively collected. The association between GPNMB protein expression level on the primary tumor and the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier analysis was used to investigate the association between GPNMB expression and the prognosis of the patients. The effects of GPNMB inhibition on cell proliferation, migration and invasion in RCC cells were investigated using short hairpin (sh)RNA. High GPNMB expression level was significantly associated with the number (P=0.001) and the extent of BM (P=0.001), Fuhrman grade (P=0.037), and ERK expression level (P=0.003) of the primary tumor. In addition, GPNMB overexpression was significantly associated with poor prognosis with respect to overall survival time (P=0.001). Furthermore, a specific shRNA sequence targeting the GPNMB gene was constructed and transduced into the ACHN cell line, using a lentivirus vector to obtain a stable cell line with low mRNA expression level of GPNMB. Low GPNMB expression level inhibited RCC cell proliferation, which was measured using a Cell Counting Kit-8 assay. Cell migration and invasion ability was significantly decreased in GPNMB knockdown RCC cells compared with that in cells transduced with the negative control shRNA. In addition, the protein expression levels of phosphorylated ERK were lower in the GPNMB shRNA-transduced ACHN cells compared with those in the control cells. Therefore, these results suggested that GPNMB plays an important role in tumor progression in RCC with BM. Furthermore, it might serve as a predictive marker for BM and as a poor prognostic factor in RCC with BM. GPNMB downregulation suppressed the proliferation, migration and invasion of the RCC cells, which may be mediated through the inhibition of the ERK signaling pathway.