Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases

Breast cancer metastasis to bone results in pain, pathological fractures and hypercalcemia. Activation of osteoclasts is critical for the formation of osteolytic lesions by metastasizing tumors. Although the potent drugs, zoledronic acid and Denosumab were introduced, the presence of resistant or intolerant cases necessitated the continued search of osteoclast-targeting treatments. Rapamycin acts through the mTOR pathway, which is important for osteoclast formation. Mouse mammary carcinoma 4T1 cells were injected into the tibia of balb/c mice. Rapamycin treatment significantly decreased the osteoclast population and osteolysis associated with experimental metastases. Our data indicate the benefit of rapamycin in treating metastases-associated osteolytic disease.     

The relationship between urinary pyridinoline, deoxypyridinoline and bone metastasis in a rat breast cancer model

Background  Bone metastasis from breast cancer is often recognized clinically, but there are nonetheless several difficulties in diagnosis. In this study we used an animal model of bone metastasis from breast cancer and clarified the relationship between the urinary Pyd/Cr and Dpd/Cr and the progression of bone metastasis, compared with other bone related markers: serum alkaline phosphatase bone isozyme (ALP-BI), osteocalcin, and calcium. Methods  The evaluation of bone metastasis was assessed by histological examination of the thoracic and lumbar vertebrae. According to the histological findings 4 weeks after the tumor cell injection, 1 1 animals were retrospectively divided into 2 subgroups: (1) tumor-bearing rats with bone destruction due to bone metastasis (TBR-BD(+), n=5), (2) tumor-bearing rats without bone destruction (TBR-BD(-), n = 6). These animals were compared to age-matched controls without tumor cell injection (n=6). An additional 5 animals were sacrificed at 2 weeks after the tumor cell injection to evaluate micrometastasis to bone. Results  The values of other markers for bone metastasis in animals with micrometastatic foci in bone marrow did not differ significantly from those of the controls. Pyd/Cr and Dpd/Cr in the TBR-BD(+) group were significantly higher than those of the TBR-BD(-) and the control group (233 + 78.3 vs 93.8±6.5, 98.5±18.7, 123.1 ±35.9 vs 67.9±6.2, 60.6±9.8, p<0.01), while there were no significant differences between TBR-BD(-) and the control. Conclusions  Both Pyd/Cr and Dpd/Cr are correlated significantly with the volume of bone metastasis, and are useful for the diagnosis and evaluation of progression of bone metastasis compared with other markers.     

Bone metabolic markers in bone metastasis of breast cancer

Background. The efficacy and cost-performance benefit of radionuclide bone scintigraphy in monitoring metastatic bone activity remain controversial. Bone metabolic markers are now expected to play a role in the diagnosis and follow-up of bone metastasis. Methods. We investigated several bone metabolic markers in patients with breast cancer. We measured three metabolic markers of bone resorption: pyridinoline cross-linked carboxy terminal telopeptide (ICTP), C-telopeptides of type I collagen (CTx), and the free form of deoxypyridinoline (fDPD), and four metabolic markers of bone formation: procollagen I carboxy terminal peptide (PICP), total alkaline phosphatase (Al-p), bone-specific alkaline phosphatase (BAl-p), and osteocalcin (BGP) in 210 patients without and 268 patients with bone metastasis. Patients without bone metastasis were analyzed in terms of menstruation status. Patients with bone metastasis were analyzed in terms of bone metastatic burden and tumor lesion "condition" (ie, determination by X-ray and/or computed tomography and bone scan findings of new lesion, progression of disease, no change, improvement, and complete remission, according to the criteria of the International Unite Against Cancer). Results. In patients without bone metastasis, ICTP did not change with menopause. All markers other than ICTP were significantly elevated with menopause. In patients with bone metastasis, all markers, except for BGP, were significantly elevated according to metastatic bone tumor burden. Among the seven markers, ICTP showed the best receiver operating characteristic curves. ICTP also showed the best correlation to bone metastatic burden among the markers by Spearman's rank correlation coefficient. In patients stratified by "condition", ICTP, CTx, fDPD, Al-p, and BAl-p showed significant elevation in patients with progression, new lesion, and no change, while PICP and BGP showed only minimal elevation in those patients. Conclusion. Bone metabolic markers, particularly ICTP, appear to be valuable for the diagnosis of bone metastasis from breast cancer. Received: April 22, 1999 / Accepted: July 15, 1999     

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.     

肿瘤标志物与乳腺癌骨转移的诊治

 骨转移是乳腺癌远处转移的最常见部位，及时和准确的诊断和治疗对提高患者生活质量、延长生存期具有重要意义。近年来，肿瘤标志物在乳腺癌骨转移中的作用日益受到重视。对部分肿瘤标志物在乳腺癌骨转移诊断、治疗以及疗效监测等方面研究进展进行了综述。     

Inhibition of bone metastasis from breast cancer with pamidronate resulting in reduction of urinary pyridinoline and deoxypyridinoline in a rat model

BACKGROUND: Breast cancers frequently metastasize to bone, in a process in which osteoclasts play a major role. Bisphosphonate pamidronate, a specific inhibitor of osteoclasts, has been widely used in the treatment of bone metastasis (BM). In this study, using an animal model of BM, we examined the prophylactic and treatment effects of pamidronate against BM and clarified the relationships between BM, pamidronate and bone resorption markers such as urinary pyridinoline and deoxypyridinoline. METHODS: Bone metastases were established by inoculating c-SST-2 (spontaneously developed rat mammary adenocarcinoma) cells into the thoracic aorta of 27 rats, which were then divided into three groups of rats: the untreated control group, the pre-treatment group, consisting of rats treated with pamidronate (10 mg/kg) injected subcutaneously a day before tumor inoculation, and the post-treatment group, in which rats were injected with pamidronate a week after tumor inoculation. Three weeks after tumor inoculation, blood and urine samples were collected. The subjects were then sacrificed to harvest the thoracic and lumbar vertebrae for histological examination, consisting of staining with hematoxylin and eosin and tartrate resistant acid phosphatase (TRACP). RESULTS: The incidence of BM was 70.0%, 44.4% and 37.5% in the control, pre-treatment and post-treatment groups, respectively. Although there was no significant difference among the groups, the rate of BM in the treated groups was lower than that of the control group and no bone destruction was observed in treated rats. The TRACP-stained specimens revealed that there were numerous osteoclasts contributing to the control group tumor burden. The urinary levels of pyridinoline and deoxypyridinoline were reduced by pamidronate. CONCLUSION: Our results suggest that pamidronate prevents the development of BM and the destruction of bone associated with BM. Maintaining the values of Pyr and Dpyr at low levels with pamidronate might lead to inhibition of the incidence and development of BM.     

乳腺癌骨转移药物治疗的现状和进展

乳腺癌骨转移的发生率较高,应根据具体病情制订个体化的综合治疗方案,以减少或避免骨相关事件、延长患者的生存期、改善生活质量。其主要治疗手段包括抗肿瘤治疗、骨改良药物治疗、手术、放疗、止痛和支持治疗等。本文就乳腺癌骨转移的药物治疗作一综述。     

乳腺癌骨转移研究的新进展及展望——从机制到临床

乳腺癌骨转移是晚期乳腺癌患者严重的并发症之一.骨转移后出现的严重骨痛、病理性骨折等并发症,严重影响患者的生活质量并缩短其生存期.近年来,随着对乳腺癌骨转移机制以及肿瘤细胞与骨微环境之间相关调控网络的认知不断深入,许多新药的开发和应用使乳腺癌骨转移的治疗取得重大进展.现就乳腺癌骨转移机制及目前治疗研究进展进行综述.     

乳腺癌骨转移内分泌治疗与化疗的对比研究

目的　对比分析内分泌治疗与化疗对乳腺癌骨转移的疗效。方法　对 138例无内脏转移的乳腺癌骨转移患者 ,行 2 89例次单独内分泌治疗或化疗。结果　内分泌治疗与化疗的一线治疗有效率分别为 35 .4 %和 31.7% ,差异无显著性 (χ2 =0 .16 3,P =0 .6 87) ;全部治疗有效率分别为 2 7.1%和 2 5 .0 % ,差异无显著性 (χ2 =0 .15 9,P =0 .6 90 ) ;临床获益率分别为 4 3.9%和 36 .6 % ,差异无显著性(χ2 =0 .6 0 3,P =0 .4 37)。但内分泌治疗与化疗的二线治疗临床获益率分别为 4 7.8%和 2 4 .2 % ,全部治疗为 4 7.5 %和 2 7.7% ,差异均有显著性 (χ2 =4 .5 37,P =0 .0 33;χ2 =11.2 0 1,P =0 .0 0 1)。内分泌治疗和化疗患者的中位治疗失败时间 (TTF)为 5个月和 2个月 ,中位病变进展时间 (TTP)为 5个月和 2 .5个月 ,差异均有非常显著性 (P均 <0 .0 0 1)。结论　单独内分泌治疗和化疗均为乳腺癌骨转移的有效治疗手段 ,其中内分泌治疗优于化疗。     

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.     

骨唾液酸蛋白与乳腺癌骨转移相关性的研究进展

多项研究已证实骨唾液酸蛋白(BSP)与乳腺癌骨转移具有相关性,而目前研究的热点是BSP诱导乳腺癌骨转移的具体作用机制及参与BSP基因表达调控的因子种类,这将为今后研究治疗骨转移相应靶向药物提供直接理论依据。同时将BSP与其他骨代谢指标如OPN、TRACP5b、NTx、PTHrP等联合检测可提高乳癌骨转移高风险人群筛选的精确性,并且这些因子可以作为乳腺癌的独立预后因素。     

改良EDTA脱钙法和酸脱钙法在乳腺癌骨转移免疫组织化学中的比较研究

背景与目的：晚期乳腺癌骨转移发生率大于70%,对骨组织进行脱钙处理是一大技术难点。探索乳腺癌骨转移的临床特点及更适合对骨组织进行脱钙的方法。方法：收集2012年1月—2018年1月期间病理学诊断为乳腺癌骨转移患者的临床资料,分析临床特征;分析改良乙二胺四乙酸二钠（ethylenediaminetetraacetic acid,EDTA）脱钙法及酸脱钙法对骨转移组织进行处理后,骨组织形态、结构的差异;比较两组原发灶与转移灶免疫组织化学检查结果中雌激素受体（estrogenreceptor,ER）、孕激素受体（progesterone receptor,PR）的一致性;分析两组骨转移组织ER、PR、Ki-67的阳性率;分析乳腺癌骨转移患者ER、PR阳性和阴性的生存差异。结果：116例乳腺癌骨转移患者中91.4%为溶骨性骨转移,80.1%骨转移的数量为4~20,81.9%发生骨相关事件（skeletal-related event,SRE）。41例为改良EDTA脱钙,75例为酸脱钙,两组骨组织的形态结构无明显差异。改良EDTA脱钙组ER一致性为95.1%,明显高于酸脱钙组（69.3%）（P<0.05）;改良EDTA脱钙组骨组织ER的阳性率为90.2%,明显高于酸脱钙组（73.3%）（P<0.05）;改良EDTA组PR的阳性率（58.5%）明显高于酸脱钙组（36.0%）（P<0.05）,Ki-67增殖指数明显高于酸脱钙组（P<0.05）;骨转移组织ER + 患者的平均生存时间为（41.09±4.26）个月,明显优于ER - 患者［（25.81±5.71）个月］（P<0.05）。结论：乳腺癌骨转移多为多发溶骨性,且SRE发生率高。改良EDTA脱钙法优于酸脱钙法,更适于对骨组织进行脱钙和免疫组织化学制片。     

血管生成抑制剂TNP-470对小鼠肉瘤肺转移模型的影响

目的　建立肉瘤血行肺转移模型 ,探讨血管生成抑制剂TNP 470对肉瘤肺转移的形成及生长的影响。方法　筛选经反复小鼠腹腔注射 ,能持续引起小鼠血性腹水的S 1 80腹水癌细胞。按每鼠 1 .6× 1 0 6 / 0 .2ml经尾静脉接种于 1 5g左右的离乳幼鼠后随机分为对照组及TNP 470治疗组 ,每组 1 0只。接种后 2 4h起隔天皮下注射给药 ,第 1 5天处死小鼠 ,称肺湿重。肺组织切片 ,镜下计转移灶数。结果　经筛选的S 1 80肉瘤细胞尾静脉注射可成功建立小鼠血行肺转移模型。TNP 470 1 0 0mg/kg可有效减少小鼠肺转移模型中转移灶的数目并抑制转移灶的增大 ,但尚不能完全抑制转移灶的形成。结论　使用TNP 470等血管生成抑制剂可有效抑制肿瘤血行转移灶的形成和生长     

Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model

Glypican-3 (GPC3), a proteoglycan bound to the cell membrane through a GPI anchor, is widely expressed in the embryo but down regulated in most adult tissues, with some exceptions as mammary cells. GPC3 is involved in the regulation of cell proliferation and survival in specific cell types. LM3, a murine mammary tumor cell line unable to express GPC3, was stably transfected with the rat GPC3 gene to analyze its role in tumor progression. Upon injection into syngeneic BALB/c mice LM3-GPC3 clones showed less local invasiveness and developed fewer spontaneous and experimental lung metastasis than controls. GPC3-expressing cells were more sensitive to apoptosis induced by serum depletion, exhibited a delay in the first steps of spreading and were less motile than controls. On the other hand, LM3-GPC3 cells were significantly more adherent to FN than control ones. We observed that GPC3 transfectants presented a higher expression of E-cadherin and -catenin, molecules whose down regulation has been associated with tumor progression. Exogenous TGF- increased MMP-9 activity in both control and GPC3-expressing cells, but did not modulate MMP-2. Contrarily, GPC3 expression prevented the increase of MMP-2 activity induced by IGF-II. Our results suggest that GPC3 has a protective role against mammary cancer progression.     

Omic-profiling in breast cancer metastasis to bone: Implications for mechanisms,biomarkers and treatment

Despite well-recognised advances in breast cancer treatment, there remain substantial numbers of patients who develop metastatic disease, of which up to 70% involves spread to bone, resulting in skeletal complications which have a major negative impact on mortality and quality of life. Bisphosphonates and newer bone-targeted agents have reduced the prevalence of skeletal complications, yet there remains significant unmet clinical need, particularly for the development of more specific therapies for the prevention and treatment of metastatic bone disease, for the prediction of risk of its development in individual patients and for the prediction of response to treatments.     

乳腺癌骨转移和骨相关疾病临床诊疗专家共识(2008版)

乳腺癌骨转移在复发转移乳腺癌中的发生率为65%～75%.乳腺癌远处转移中,首发症状为骨转移者占27%～50%.骨痛、骨损伤、骨相关事件(skeletal related event,SRE)的发生及生活质量的降低是乳腺癌骨转移的常见并发症.SHE是指在临床试验中表明双膦酸盐类药物治疗失败的研究观察终点,一般定义为骨痛加剧或出现新的骨痛、病理性骨折、椎体压缩或变形、脊髓压迫、骨放疗、骨转移病灶进展及高钙血症等事件,是影响患者自主活动能力和生活质量的主要因素[1-3].     

Osteotropic cancers: from primary tumor to bone

It has long been recognized that primary cancers spread to distant organs with characteristic preference. Bone metastases occur in approximately 70% of patients with advanced breast and prostate cancer, causing severe morbidity and hospitalization. In the last decade, we have gained a better understanding of the mechanisms by which certain tumor types tend to metastasize specifically to bone. It appears that the interaction between the organ microenvironment and cancer cells is fundamental for establishing metastatic growth. Accordingly, Stephen Paget's 'seed and soil' hypothesis - stating that circulating cancer cells (the 'seeds') disperse in all directions, but can accomplish metastases only in organs where the microenvironment (the 'soil') is permissive for their growth - still holds forth today. For this reason, this review uses the 'seed and soil' hypothesis as a template to discuss novel insight and developments in the bone metastasis field.     

博宁及博宁联合化疗治疗乳腺癌骨转移的疗效分析

目的观察博宁单独使用与博宁联合化疗对乳腺癌骨转移引起的疼痛、活动功能障碍及转移病灶修复的疗效.方法 56例乳腺癌骨转移患者随机分为治疗组(博宁单独应用)与对照组(博宁加化疗组),每组28例.治疗组单独静脉滴注博宁60 mg,2周后重复,连用6次或以上;对照组分别于第1、3、5次应用博宁后第3天开始采用CAF联合方案化疗,连用3周期或以上.结果止痛作用:治疗组显效10例,有效13例,总有效率82.1%;对照组显效12例,有效14例,总有效率92.9%,差异无显著性(P＞0.05).活动能力改善情况:治疗组显效9例,有效12例,总有效率75.0%;对照组显效10例,有效14例,总有效率85.7%,差异无显著性(P＞0.05).骨转移病灶修复情况:治疗组仅2例达到PR,有效率7.1%;对照组CR 1例,PR 7例,总有效率28.6%,差异有显著性(P＝0.036).结论单用博宁对乳腺癌骨转移引起的疼痛及活动障碍有较好的治疗作用,对转移病灶的修复作用甚微.博宁联合化疗可以提高疗效,并可促进骨转移灶的修复.