Osteoprotegerin diminishes advanced bone cancer pain

Bone cancer pain most commonly occurs when tumors originating in breast, prostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 400,000 new cancer cases per year in the United States alone, and >70% of patients with advanced breast or prostate cancer have skeletal metastases. Whereas pain resulting from bone cancer can dramatically impact an individual's quality of life, very little is known about the mechanisms that generate and maintain this pain. To begin to define the mechanisms that give rise to advanced bone cancer pain, osteolytic 2472 sarcoma cells or media were injected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using dental amalgam, confining the tumor cells to the bone. Twelve days after injection of 2472 tumor cells, animals showed advanced tumor-induced bone destruction of the injected femur, bone cancer pain, and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. Administration of osteoprotegerin, a naturally secreted decoy receptor that inhibits osteoclast maturation and activity and induces osteoclast apoptosis, or vehicle was begun at 12 days, when significant bone destruction had already occurred, and administration was continued daily until day 21. Ongoing pain behaviors, movement-evoked pain behaviors, and bone destruction were assessed on days 10, 12, 14, 17, and 21. The neurochemistry of the spinal cord was evaluated at days 12 and 21. Results indicated that osteoprotegerin treatment halted further bone destruction, reduced ongoing and movement-evoked pain, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of bone cancer, ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction.     

Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption

Prostate cancer preferentially metastasizes to bone, resulting in high mortality. Strategies to inhibit prostate cancer metastasis include targeting both tumor-induced osteoblastic lesions and underlying osteoclastic activities. We and others have previously shown that blocking receptor activator of nuclear factor-kappaB ligand (RANKL) partially blocks tumor establishment and progression in bone in murine models. However, levels of RANKL in the cell lines used in these studies were very low, suggesting that soluble factors other than RANKL may mediate the cancer-induced osteoclast activity. To identify these factors, a human cytokine antibody array was used to measure cytokine expression in conditioned medium collected from primary prostate epithelial cells (PrEC), prostate cancer LNCaP and its derivative C4-2B, and PC3 cells. All prostate cancer cells produced high amounts of monocyte chemotactic protein-1 (MCP-1) compared with PrEC cells. Furthermore, levels of interleukin (IL)-6, IL-8, GROalpha, ENA-78, and CXCL-16 were higher in PC3 than LNCaP. These results were confirmed by ELISA. Finally, human bone marrow mononuclear cells (HBMC) were cultured with PC3 conditioned medium. Although both recombinant human MCP-1 and IL-8 directly stimulated HBMC differentiation into osteoclast-like cells, IL-8, but not MCP-1, induced bone resorption on dentin slices with 21 days of culture in the absence of RANKL. However, the conditioned medium-induced bone resorption was inhibited by MCP-1 neutralizing antibody and was further synergistically inhibited with IL-8 antibody, indicating that MCP-1, in addition to IL-8, mediates tumor-induced osteoclastogenesis and bone resorption. MCP-1 may promote preosteoclast cell fusion, forming multinucleated tartrate-resistant acid phosphatase-positive osteoclast-like cells. This study may provide novel therapeutic targets for treatment of prostate cancer skeletal metastasis.     

Nerve growth factor is a potential therapeutic target in breast cancer

We show here that nerve growth factor (NGF), the prototypic neurotrophin, can be targeted in breast cancer to inhibit tumor cell proliferation, survival, and metastasis. Analysis of a series of biopsies revealed widespread expression of NGF in the majority of human breast tumors, with anti-NGF immunoreactivity concentrated in the epithelial cancer cells. Moreover, immunodeficient mice xenografted with human breast cancer cells and treated with either anti-NGF antibodies or small interfering RNA against NGF displayed inhibited tumor growth and metastasis. Such treatments directed against NGF induced a decrease in cell proliferation with a concomitant increase in apoptosis of breast cancer cells and an inhibition of tumor angiogenesis. Together, these data indicate that targeting NGF in breast cancer may have therapeutic ramifications.     

Augmented Osteolysis in SPARC-Deficient Mice with Bone-Residing Prostate Cancer

Prostate cancer preferentially metastasizes to bone, which is rich in structural and matricellular proteins capable of altering prostate cancer progression. This study explores the role of the bone stromal matricellular protein SPARC (osteonectin/BM-40) in the progression of bone metastatic prostate cancer. Quantification of bone destruction analyzed by micro-computed tomography showed augmented osteoclastic resorption, characterized by decreases in several morphometric bone parameters in SPARC knock out (KO) tibiae harboring RM1 murine prostate cancer cells compared with wild type (WT) animals. Tumor progression stimulated osteoclast formation, which was augmented in SPARC KO mice. In vitro differentiation of SPARC KO osteoclasts indicated accelerated progenitor expansion and formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells with increased resorptive capacity, a mechanism resulting in enhanced tumor-induced bone loss in vivo. Whereas altered bone structure due to SPARC KO played a role in increased osteolysis, the enhanced osteolysis was primarily the result of increased resorption by SPARC KO osteoclasts. Our findings indicate that bone stromal SPARC suppresses tumor-induced bone lesion expansion by limiting osteoclast maturation and function.     

Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism

Prostate cancer frequently metastasizes to bone where it forms osteoblastic lesions through unknown mechanisms. Bone morphogenetic proteins (BMP) are mediators of skeletal formation. Prostate cancer produces a variety of BMPs, including BMP-6. We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites. Prostate cancer cells and clinical tissues produced BMP-6 that increased with aggressiveness of the tumor. Prostate cancer-conditioned medium induced SMAD phosphorylation in the preosteoblast MC3T3 cells, and phosphorylation was diminished by anti-BMP-6 antibody. Prostate cancer-conditioned medium induced mineralization of MC3T3 cells, which was blocked by both the BMP inhibitor noggin and anti-BMP-6. Human fetal bones were implanted in severe combined immunodeficient mice and after 4 weeks, LuCaP 23.1 prostate cancer cells were injected both s.c. and into the bone implants. Anti-BMP-6 or isotype antibody administration was then initiated. Anti-BMP-6 reduced LuCaP 23.1-induced osteoblastic activity, but had no effect on its osteolytic activity. This was associated with increased osteoblast numbers and osteoblast activity based on bone histomorphometric evaluation. As endothelin-1 has been implicated in bone metastases, we measured serum endothelin-1 levels but found they were not different among the treatment groups. In addition to decreased bone production, anti-BMP-6 reduced intraosseous, but not s.c., tumor size. We found that BMP-2, BMP-4, BMP-6, and BMP-7 had no direct effect on prostate cancer cell growth, but BMP-2 and BMP-6 increased the in vitro invasive ability of prostate cancer cell. These data show that prostate cancer promotes osteoblastic activity through BMP-6 and that, in addition to its bone effects, suggest that BMPs promote the ability of the prostate cancer cells to invade the bone microenvironment.     

Clinical utility of radiolabeled monoclonal antibodies in prostate cancer

Prostate cancer represents an ideal target for radioimmunotherapy based on the pattern of spread, including bone marrow and lymph nodes, sites that typically receive high levels of circulating antibody, and the small volume of disease, ideally suited for antibody delivery and antigen access. This review explores possible antibody targets in prostate cancer and focuses on the potential role for radioimmunotherapy by highlighting several clinical trials involving radiolabeled anti-prostatespecific membrane antigen monoclonal antibody J591. Prostate-specific membrane antigen, a highly prostate-restricted transmembrane glycoprotein with increased expression in high-grade, metastatic, and hormone-refractory disease, represents an ideal target for monoclonal antibody therapy in prostate cancer. Radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591 trials using the radiometals yttrium-90 and lutetium-177 have demonstrated manageable myelotoxicity, no significant nonhematologic toxicity, excellent targeting of soft-tissue and bone metastases, and preliminary efficacy including prostate-specific antigen and measurable disease responses. Additional studies are under way to better define the activity of radiolabeled antibody therapy as well as the role for fractionated therapy and combination approaches with taxane-based chemotherapy.     

Clinical Utility of Radiolabeled Monoclonal Antibodies in Prostate Cancer

Prostate cancer represents an ideal target for radioimmunotherapy based on the pattern of spread, including bone marrow and lymph nodes, sites that typically receive high levels of circulating antibody, and the small volume of disease, ideally suited for antibody delivery and antigen access. This review explores possible antibody targets in prostate cancer and focuses on the potential role for radioimmunotherapy by highlighting several clinical trials involving radiolabeled anti–prostatespecific membrane antigen monoclonal antibody J591. Prostate-specific membrane antigen, a highly prostate-restricted transmembrane glycoprotein with increased expression in high-grade, metastatic, and hormone-refractory disease, represents an ideal target for monoclonal antibody therapy in prostate cancer. Radiolabeled anti–prostate-specific membrane antigen monoclonal antibody J591 trials using the radiometals yttrium-90 and lutetium-177 have demonstrated manageable myelotoxicity, no significant nonhematologic toxicity, excellent targeting of soft-tissue and bone metastases, and preliminary efficacy including prostate-specific antigen and measurable disease responses. Additional studies are under way to better define the activity of radiolabeled antibody therapy as well as the role for fractionated therapy and combination approaches with taxane-based chemotherapy.     

Pelvic cancer pain

Pelvic cancer causes several types of pain, i.e., visceral, neuropathic, and somatic pain. Somatic pain is due to stimulation of nociceptors in the integument and supporting structures, namely, striated muscles, joints, periosteum, bones, and nerve trunks by direct extension through fascial planes and their lymphatic supply. In 60% of patients with malignant disease of soft tissues, nerve trunk, and sacral invasion from carcinoma of the cervix, uterus, vagina, colon, rectum, and other tissues in women, and from penile, prostate, and colorectal carcinoma and sarcoma in men, they have neuropathic pain. The infiltration of the perineal nerves results in lumbosacral plexopathies and complete destruction of the nerve, including perineural lymphatic invasions producing symptomatic sensory loss, causalgia, and deafferentation. Visceral pain is the result of spasms of smooth muscles of hallow viscus; distortion of capsule of solid organs; inflammation; chemical irritation; traction or twisting of mesentery; and ischemia, or necrosis, and encroachment of pelvis and presacral tumors. Pain of these types is managed by different modalities depending on the age of the patient, the expected life expectancy, availability of invasive and non-invasive pain control modalities, and the resources of the patient, community, and health care agencies. Patients with pelvic cancer can live with less pain due to better pain-control modalities that are available today with the help of dedicated and caring algologists.     

The role of abiraterone in the management of metastatic castration-resistant prostate cancer

Prostate cancer is the most common solid-organ cancer affecting the male population. Men with metastatic prostate cancer treated with androgen ablation therapy often respond rapidly, with improvement in bone pain and decreases in serum prostate-specific antigen. However, almost all patients progress to the castrate-resistant state and until recently chemotherapy was the only treatment available with proven survival benefit. Abiraterone is a new class of anti-androgen with proven survival benefit post-chemotherapy. In this review we discuss the characteristics of abiraterone and the clinical trials that led to its approval for the treatment of patients with prostate cancer.     

Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling

The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the alphavbeta3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that alphavbeta3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional alphavbeta3 enabled tumor growth in bone (incidence: 4/4), whereas alphavbeta3 (-), inactive or constitutively active mutants of alphavbeta3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated alphavbeta3 (either inactive of constitutively active), but not those lacking beta3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for beta3 integrin, we next demonstrated that alphavbeta3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated alphavbeta3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.     

基于脊髓层面的骨癌痛发生机制

骨癌痛动物模型的不断出现和日渐完善为癌痛机制研究提供了有效的工具,癌痛的病理机制异于炎性痛和神经病理性痛,具有其独特性。全文以骨癌动物模型为载体,综述骨癌痛发生的脊髓机制。     

Pain management in patients with advanced prostate cancer

Prostate cancer is the most commonly diagnosed cancer among American men. The majority of patients with advanced disease have metastatic bone lesions, which are frequently very painful. These lesions tend to respond well to treatment with both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, although careful dose titration and individualized treatment plans may be needed to achieve maximal analgesia. Opioid side effects are often transient or well controlled with additional medication. Patients with intolerable side effects may experience fewer adverse reactions with a different opioid. Palliative radiation provides pain relief in up to 80% of prostate cancer patients with single or at most a few sites of localized bone pain. Bisphosphonates, powerful inhibitors of osteoclast-mediated bone resorption, are promising new agents for the treatment of painful bone lesions in prostate cancer patients. Radioisotopes, which deliver high-dose radiation to bone lesions without significantly affecting normal bone, are highly effective in providing some degree of pain relief in up to 80% of patients with diffuse, painful bone metastases. Also, chemotherapy shows promise in alleviating pain and possibly extending survival in patients with advanced prostate cancer.     

转移性癌性骨痛的分子机制及临床治疗研究进展

晚期癌症患者肿瘤骨转移诱发的骨痛是癌痛的最常见症状。癌性骨痛可显著影响患者的生存质量并使预后恶化。癌性骨痛包括背景痛及爆发性疼痛等多种形式,其发病机制复杂,包括炎性疼痛及神经病理性疼痛等,并随肿瘤的进展而变化。目前临床治疗主要包括外周及中枢镇痛药物、破骨细胞抑制剂等药物治疗,及放疗、神经损毁及神经调节等非药物治疗。阐明癌性骨痛的分子机制对优化治疗具有指导意义,本文将对转移性癌性骨痛的发病机制及临床治疗的进展进行综述。     

前列腺癌骨转移治疗的研究进展

前列腺癌是常见的男性泌尿系恶性肿瘤之一，而骨转移是前列腺癌常见的并发症之一。骨转移后出现严重的骨痛、病理性骨折、神经压迫等各种并发症，严重影响患者的生活质量，更决定患者的生存时间。目前关于前列腺癌骨转移治疗的文献较多，但还没有宏观上分析各种治疗方法的应用时机，未形成一个大家都认同的标准化治疗方案。本文就通过前列腺癌骨转移的分类来制定治疗方案作一综述。     

Pathophysiology of bone cancer pain

The most common cancers, such as those affecting the breast, prostate, and lung have a strong predilection to metastasize to bone. Bone metastasis frequently results in pain, pathologic fractures, hypercalcemia, and spinal cord compression. Pain can have a devastating effect on the quality of life in advanced cancer patients and is a serious complication of cancer. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of bone cancer pain is poorly understood. New insights into the mechanisms that induce cancer pain now are coming from animal models.Chemicals derived from tumor cells, inflammatory cells, and cells derived from bone appear to be involved simultaneously in driving this frequently difficult-to-control pain state. Understanding the mechanisms involved in the pathophysiology of bone cancer pain will improve both our ability to provide mechanism-based therapies and the quality of life of cancer patients.     

Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates

Patients with prostate cancer are at risk for skeletal complications resulting from treatment-induced bone loss and for bone metastases. The therapeutic potential of zoledronic acid for the treatment of prostate cancer has been demonstrated in both preclinical and clinical studies. In patients receiving androgen-deprivation therapy, zoledronic acid increases bone mineral density, and, in patients with bone metastases, it reduces the incidence of skeletal complications. Preclinical studies have also demonstrated the antitumor potential of bisphosphonates. Specifically, zoledronic acid inhibits proliferation and induces apoptosis of human prostate cancer cell lines in vitro and has enhanced antitumor activity when combined with taxanes. Animal models have further shown that bisphosphonates decrease tumor-induced osteolysis and reduce skeletal tumor burden. In a model of prostate cancer, zoledronic acid significantly inhibited growth of both osteolytic and osteoblastic tumors and reduced circulating levels of prostate-specific antigen. These studies suggest that zoledronic acid has the potential to inhibit bone metastasis and bone lesion progression in patients with prostate cancer.     

Management of complications of prostate cancer treatment.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in men in the United States. Treatment of men with prostate cancer commonly involves surgical, radiation, or hormone therapy. Most men with prostate cancer live for many years after diagnosis and may never suffer morbidity or mortality attributable to prostate cancer. The short-term and long-term adverse consequences of therapy are, therefore, of great importance. Adverse effects of radical prostatectomy include immediate postoperative complications and long-term urinary and sexual complications. External beam or interstitial radiation therapy in men with localized prostate cancer may lead to urinary, gastrointestinal, and sexual complications. Improvements in surgical and radiation techniques have reduced the incidence of many of these complications. Hormone treatment typically consists of androgen deprivation therapy, and consequences of such therapy may include vasomotor flushing, anemia, and bone density loss. Numerous clinical trials have studied the role of bone antiresorptive therapy for prevention of bone density loss and fractures. Other long-term consequences of androgen deprivation therapy may include adverse body composition changes and increased risk of insulin resistance, diabetes, and cardiovascular disease. Ongoing and planned clinical trials will continue to address strategies to prevent treatment-related side effects and improve quality of life for men with prostate cancer.     

A prospective study of prostate specific antigen levels in patients receiving radiotherapy for localized carcinoma of the prostate.

Prostate Specific Antigen (PSA) is becoming the preferred tumor marker in the management of prostate cancer. Prostate Specific Antigen levels fall exponentially after radical prostatectomy with a half-life of between 2 and 3 days. Persistently elevated Prostate Specific Antigen levels beyond 7 half-lives suggest occult residual disease and may serve as an indication for post operative adjunctive therapy. The change in Prostate Specific Antigen levels during a course of radical external beam radiotherapy for prostate cancer has not been described. In this study of 81 patients receiving radiotherapy for primary prostate cancer, 47 had elevated Prostate Specific Antigen levels prior to therapy and 35 had serial measurement of Prostate Specific Antigen during their course of treatment. Working on an assumption that in patients with radioresponsive localized prostate cancer Prostate Specific Antigen levels will fall exponentially during the radiotherapy, a half-life of 43 +/- 11 days was derived. Prostate Specific Antigen half-life appears independent of stage, grade, or pretreatment Prostate Specific Antigen level and may be an independent prognostic indicator. A prolonged Prostate Specific Antigen half-life may suggest untreated or resistant disease and serve as an indication for adjuvant hormonal treatment in patients receiving radiotherapy for primary prostate cancer.     

Can palliative radiotherapy influence prostate-specific antigen response in patients with castrate-resistant prostate cancer treated with systemic therapy (chemotherapy or abiraterone)?—a report of three cases

Palliative radiotherapy (pRT) is primarily employed for palliation of bone pain in patients with castrate-resistant prostate cancer (CRPC). However, evidence that pRT influences prostate-specific antigen response in patients with CRPC on systemic therapy is lacking. We describe three cases of CRPC progressing after treatment with docetaxel (n=2) and abiraterone (n=1), who responded unusually after pRT for bone pain with the development of a significant biochemical response and restoration of response to systemic therapy. The possibility of pRT influencing metastatic disease in CRPC has not been previously reported, and raises the possibility of radiation-induced modulation of anti-tumor immune response mechanisms that may play a role in the restoration of response to systemic treatment.KEYWORDS : Prostate cancer, palliative, radiotherapy, chemotherapy     

Prostate cancer, serum parathyroid hormone, and the progression of skeletal metastases

Bony metastases from prostate cancer are a significant cause of morbidity and mortality. These metastases are predominantly blastic (bone-forming) and commonly cause increased serum levels of parathyroid hormone (PTH) as calcium ions are transferred from serum into blastic bone. The epidemiologic and clinical significance of secondary hyperparathyroidism in advanced prostate cancer have not been widely appreciated. Prostate cancer bony metastases show increased expression of the PTH receptor (PTH-IR) and PTH promotes the growth and invasiveness of prostate cancer cells in bone. Thus, blastic metastases appear to induce a "vicious cycle" in which PTH resorbs normal bone to support the growth of blastic bone. Recognition of the potential role of PTH in the progression of skeletal metastases suggests novel opportunities for prostate cancer secondary prevention. In particular, we propose that suppressing serum PTH in advanced prostate cancer may reduce morbidity by decreasing fractures and pain caused by bone resorption and may reduce mortality by retarding the progression of metastatic disease.