Intraosseous growth of human prostate cancer in implanted adult human bone: relationship of prostate cancer cells to osteoclasts in osteoblastic metastatic lesions

BACKGROUND: More than 80% of patients with advanced prostate cancer have skeletal involvement, but the biology of bone metastasis is poorly understood. This study investigated the in vivo formation and progression of bone metastases under conditions that resembled the human bone environment as closely as possible. METHODS: Adult human bone fragments were implanted subcutaneously into 120 male NOD/SCID mice. Four weeks later, 1 x 10(7) LNCaP prostate cancer cells or phosphate-buffered saline were injected intravenously into 80 or 40 mice, respectively. The implanted bone fragments were removed from 20 to 10 mice in each group at 2, 4, 6, and 8 weeks after injection. RESULTS: LNCaP colonized the bone marrow blood vessels within 2 weeks, and then gradually expanded into the entire medullary cavity. An osteoblastic response often occurred at the edges of metastatic foci (intertrabecular bone metaplasia). In addition, new bone formation was observed adjacent to mature lamellar bone (appositional bone formation). These two processes appeared to occur through different mechanisms, but might similarly cause osteosclerosis. Osteoclasts showed a marked increase in numbers at sites of early tumor invasion, whereas few osteoclasts were observed at sites where tumor invasion was complete. CONCLUSIONS: The predominance of osteoblastic change with resorption may lead to bone remodeling in metastatic lesions, and osteoclasts may play an important role in bone metastasis from prostate cancer.     

^99mTc—MDP骨扫描在前列腺癌骨转移诊断中的价值

目的：探讨^99mTc-MDP骨扫描在前列腺痛骨转移诊断中的价值。方法：对明确诊断为前列腺癌的527例患者行^99mTc-MDP骨扫描,骨扫描不能确诊为骨转移者再经MRI、CT和病理检查等最后确诊有无骨转移。结果：在527例前列腺癌^99mTc-MDP骨扫描中,阳性显像331例,阴性显像196例;最后确诊骨转移者318例,占前列腺癌总例数的60．34％（318／527）．无骨转移者209例,占前列腺癌总例数的39．66％（209／527）。^99mTc-MDP骨扫描诊断前列腺癌骨转移的灵敏度为84．59％（269／318）,特异度为70．33％（147／209）,误诊率为29．67％（62／209）．漏诊率为15．4l％（49/318）．阳性预测值为81．27％（269／331）,阴性预测值为75．00％（147／l96）。随着^99mTc-MDP骨扫描诊断前列腺癌骨转移病灶数量级别从I级增至Ⅱ级和Ⅲ级时,其诊断前列腺癌骨转移的准确度越来越高。结论：^99mTc-MDP骨扫描诊断前列腺癌骨转移具有微高的灵敏度、特异性、阳性预测值和阴性预测倩,误诊率和漏诊率低。随骨转移病灶级别的增加,其诊断前列腺癌有无骨转移的价值越来越大。     

Clinical usefulness of bone markers in prostate cancer with bone metastasis

Bone metastases occur in approximately 70% of patients with advanced prostate cancer. Skeletal‐related events have been correlated with reduced survival and quality of life of patients with prostate cancer. Biochemical markers of bone metabolism (e.g. bone formation, bone resorption, osteoclastogenesis) might meet an unmet need for useful, non‐invasive and sensitive surrogate information for following patients' skeletal health. Recently, zoledronic acid and denosumab have been proven to have the potential for preventing skeletal‐related events among prostate cancer patients with bone metastasis. An improved understanding of the mechanisms underlying bone metastasis has also led to the recognition of multiple molecular targets and advances in therapy. However, estimating the efficacy of these agents is difficult. A clinical trial for castration‐resistant prostate cancer is currently underway based on the definition of The Prostate Cancer Clinical Trials Working Group, and bone turnover markers are being used as conventional end‐points for the clinical trial. Bone turnover markers are useful surrogate markers reflecting the effect of new therapeutic drugs and prognosis, as well as assessment of bone metastases. In particular, N‐terminal cross‐linked telopeptide of type 1 collagen and bone‐specific alkaline phosphatase are widely used bone metabolism markers, and offer reliable surrogate markers to detect bone metastatic spread and to predict prognosis for prostate cancer patients with bone metastases.     

In vivo models of prostate cancer metastasis to bone

Purpose

The metastasis of prostate cancer to bone is the most significant cause of morbidity and mortality in this disease. An estimated 28,900 men die annually secondary to prostate cancer bone metastasis. Current treatments increase survival for 2 months and only bisphosphonates offer any palliative benefit. This shortcoming is due in part to inadequate models in which to study the molecular biology of the disease and evaluate therapeutic regimens. We examined the breadth of models available that recapitulate the process of prostate cancer metastasis to bone.

Materials and Methods

A PubMed search was done for publications concerning prostate cancer metastasis to bone and the imaging of bone metastases. Only studies focusing on model systems of disease progression and imaging of the process were included. Additional studies were found by cross-reference searching.

Results

Prostate cancer metastasis to bone is a lengthy, complex process characterized by multiple stages. This has made it difficult to find adequate laboratory models in which to recreate the disease process. Each available model has characteristics of particular phases of disease progression to bone. The most widely used models are transgenic mice, variations of SCID mice, and the traditional orthotopic and xenotransplantation models. Furthermore, investigators have started to adapt their models to incorporate imaging modalities for following the progression of prostate cancer to bone.

Conclusions

The development of models of prostate cancer metastasis to bone is an evolving discipline. A deeper understanding of the metastatic process has served to improve current models and it will continue to do so in the future.     

Osteoblasts produce soluble factors that induce a gene expression pattern in non-metastatic prostate cancer cells, similar to that found in bone metastatic prostate cancer cells

BACKGROUND: Progressive prostate cancer typically metastasizes to bone where prostate cancer cells gain an osteoblast-like phenotype and induce osteoblastic metastases through unknown mechanisms. To investigate the biology of prostate cancer skeletal metastases, we compared gene expression between the non-metastatic LNCaP cell line and its derivative cell line C4-2B that metastasizes to bone. METHODS: Total RNA from LNCaP and C4-2B cell lines was isolated and used to probe membrane-based gene arrays (Comparison 1). Additionally, LNCaP cells were incubated in the absence or presence of conditioned media (CM) from a human osteoblast-like cell line (HOBIT) and total RNA from these cells was used to probe gene arrays (Comparison 2). Differential expression of genes was confirmed by RT-PCR. RESULTS: Of the 1,176 genes screened, 35 were differentially expressed between LNCaP and C4-2B cells (Comparison 1). HOBIT-CM induced differential expression of 30 genes in LNCaP cells (Comparison 2). Interestingly, 19 genes that were differentially expressed in C4-2B vs. LNCaP also displayed a similar expression pattern in LNCaPs grown in HOBIT-CM. These genes are primarily involved in motility, metabolism, signal transduction, tumorigenesis, and apoptosis. CONCLUSIONS: These results suggest that osteoblasts produce soluble factors that contribute to the progression of prostate cancer skeletal metastases, including their transition to an osteoblast-like phenotype. Additionally, these data provide targets to explore for further investigations towards defining the biology of skeletal metastases.     

Magnetic resonance imaging of the axial skeleton enables objective measurement of tumor response on prostate cancer bone metastases

BACKGROUND: There is currently no technique to image quantitatively bone metastases. Here, we assessed the value of MRI of the axial skeleton (AS-MRI) as a single step technique to quantify bone metastases and measure tumor response. METHODS: AS-MRI was performed in 38 patients before receiving chemotherapy for metastatic HRPCa, in addition to PSA, computed tomography of the thorax, abdomen, and pelvis [CT-TAP]; and Tc-99m bone scintigraphy. A second AS-MRI was performed in 20 patients who completed 6 months of chemotherapy. Evaluation of tumor response was performed using RECIST. RESULTS: Only 11 patients (29%) had RECIST measurable metastases in soft-tissues or lymph nodes on baseline CT-TAP. AS-MRI identified a diffuse infiltration of the bone marrow in 8 patients and focal measurable metastatic lesions in 25 patients (65%), therefore, doubling the proportion of patients with measurable lesions. Transposing RECIST on AS-MRI in 20 patients who completed 6 months of treatment, allows the accurate estimation of complete response (n = 2), partial response (n = 2), stable disease (n = 5), or tumor progression (n = 11), as it is done using CT-TAP in soft tissue solid metastases. CONCLUSIONS: MRI of axial skeleton enables precise measurement and follow-up of bone metastases as it is for other soft-tissue metastasis.     

Treatment of androgen-independent prostate cancer with dexamethasone: A prospective study in stage D2 patients

PURPOSE: In order to evaluate the efficacy of dexamethasone in the treatment of Japanese men with androgen-independent prostate cancer, a prospective study was conducted using prostate-specific antigen (PSA) as a primary end-point. METHODS: Nineteen Japanese men with stage D2 androgen-independent prostate cancer were registered and treatment was started. After ruling out anti-androgen withdrawal syndrome, they were treated with dexamethasone (1.5 mg daily). Patients were monitored for PSA, symptoms, radiologic response, survival rate, time to disease progression, time to treatment failure and complications. RESULTS: Prostate-specific antigen levels decreased in nine patients (50.0%); five (27.8%) showed a 50% or greater decrease and two (11.1%) showed an 80% or greater decrease. For the nine patients, the mean duration of PSA response was 7.3 months and the median duration was 2.1 months (range, 1.2-27.5+). Bone pain, which was noted in 13 patients at study entry, improved in seven patients (53.8%). Of nine patients who had serial radiographic examinations with bone scan, three (33%) showed partial response, two (22%) were stable and four (44%) showed disease progression. Treatment was well tolerated, except for one patient who suffered a severe pulmonary infection. CONCLUSION: Dexamethasone decreased PSA levels and produced subjective symptomatic improvement in the patients with stage D2 androgen-independent prostate cancer.     

Effect of zoledronic acid on metastatic hormone-refractory prostate cancer resistant to taxane, estramustine, carboplatin, and dexamethasone

This case report demonstrates the effect of zoledronic acid (ZA) on a patient with bone metastatic hormone-refractory prostate cancer (HRPC) resistant to taxane, estramustine phosphate, carboplatin, and dexamethasone. The pathogenesis, diagnosis, and management of bone metastasis on HRPC are also reviewed.     

前列腺癌骨转移血清蛋白质组学研究

目的:应用蛋白质组学双向凝胶电泳和质谱技术筛选前列腺癌骨转移血清标志物。方法:收集前列腺癌伴骨转移、不伴骨转移各5例血清样本。血清样品用除白蛋白试剂盒除去血清中的白蛋白后进行双向凝胶电泳,ImageMaster 2D Platinum软件分析,有意义的差异蛋白质点行基质辅助激光解析离子化飞行时间质谱(MALDI-TOF-MS)鉴定。结果:双向凝胶电泳显示,前列腺癌骨转移组血清蛋白中有15个斑点与前列腺癌无骨转移组有显著差异,前列腺癌骨转移患者血清中10个蛋白质表达水平显著增加,5个蛋白质表达水平显著下降。5个差异蛋白点进行胶内原位酶解,肽质量指纹图谱分析成功得到了3个蛋白质肽质量指纹图谱,并查询数据库初步鉴定了该3个蛋白质分别为锌α2糖蛋白、结合珠蛋白和载脂蛋白CⅢ。结论:双向凝胶电泳结合质谱鉴定是血清差异蛋白质组学研究的可靠平台和有力工具。所鉴定出的蛋白质与前列腺癌骨转移的发生、发展有关,可能是前列腺癌骨转移潜在的血清标志物。