乳腺癌组织中 BSP 表达及意义

目的：探讨骨唾液蛋白（BSP）在乳腺癌组织中的表达状况及与相关因素年龄、淋巴结转移、骨转移、C-erbB-2的关系.方法：应用免疫组化SP法检测60例乳腺癌与60例正常乳腺组织中BSP的表达,以及在乳腺癌组织中的表达与年龄、淋巴结转移、骨转移、C-erbB-2相关因素进行分析.结果：乳腺癌组织中BSP阳性表达率为78.3%,正常乳腺组织中BSP阳性表达率为15.0%,P＜0.05有统计学差异.BSP表达与年龄、骨转移相关（P＜0.05）.结论：BSP在乳腺癌组织中高表达,与乳腺癌浸润和骨转移密切相关,能指导判断乳腺癌侵袭、转移及预后.     

BSP在原发性乳腺癌组织中的表达对预测术后骨转移的临床意义

目的:探讨BSP在原发性乳腺癌组织中的表达对预测术后骨转移的临床意义.方法:用免疫组织化学SP法测定70例原发性乳腺癌石蜡标本中BSP的表达,及ER、PR、C-erb-B2表达情况.结果:1)BSP在骨转移组表达明显高于无骨转移组(无转移组 骨外转移组)(P＜0.01),且强阳性表达高于后者(P＜0.05);同时,骨转移组与无转移组和骨外转移组之间阳性表达均有差别(P＜0.05;P＜0.01),而后两组间阳性表达无统计学差异(P＞0.05).2)BSP的表达在Ⅱ期及Ⅲ期患者组间有差异(P＜0.05),但与患者年龄及ER、PR、C-erb-B2状态,肿块大小,病理类型及淋巴结转移数目均无相关(P＞0.05).结论:在原发性乳腺癌组织水平上,BSP是早期预测术后骨转移的良好标志物.     

联合检测血清NTx和BSP对乳腺癌和肺癌骨转移的意义

摘 要 目的: 探讨骨代谢生化指标血清Ⅰ型胶原交联氨基末端肽（Ntelopeptide of type Ⅰ collagen，NTx）和骨涎酸蛋白(bone sialoprotein, BSP)的检测对肺癌和乳腺癌骨转移的临床意义。方法：选择2006年1月至2006年7月长海医院肿瘤科经病理确诊的肺癌或乳腺癌患者105例，分为两组，其中骨转移组50例，无骨转移组55例。应用ELISA法检测患者血清NTx和BSP浓度。结果：骨转移组患者血清NTx和BSP水平均明显高于无骨转移组（P<0.01）。NTx诊断骨转移的灵敏度和特异度分别为90.0％和67.3％，BSP诊断骨转移的灵敏度和特异度分别为84.0％和70.9％。临床发生骨相关事件（skeletal related event，SRE）的骨转移患者，血清NTx水平明显高于未发生SRE的骨转移患者（P<0.05）。在6~13个月随访期内，21例患者确诊了新发骨转移；采用Cox比例风险回归模型分析，血清NTx浓度升高提示骨转移发生的相对危险度为1.127；乳腺癌患者血清BSP增高是唯一预测骨转移的危险因素（P<0.05），其相对危险度为1.058。随访期共有33例患者死亡；无论肺癌还是乳腺癌，血清BSP增高患者的累积生存率均明显低于血清BSP正常组（P<0.05）。结论：血清NTx和BSP是诊断肺癌和乳腺癌骨转移的重要参考指标，其水平的增高是预测骨转移发生的高危因素；BSP可能是肺癌和乳腺癌患者独立预后指标。     

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。     

检测NTx、BSP对唑来膦酸治疗肺癌骨转移的临床意义

目的：通过检测血清NTx、BSP水平预测唑来膦酸（Zoledronic Acid）治疗肺癌骨转移的临床疗效。方法：将64例确诊为非小细胞肺癌骨转移患者使用唑来膦酸治疗。用ELISA法测定患者治疗前后血清NTx和BSP浓度。结果：使用唑来膦酸治疗后骨转移瘤好转的患者血清NTx和BSP水平显著降低（P〈0.01）;骨转移无好转者血清NTx和BSP水平变化无显著差异（P〉0.05）。结论：血清NTx、BSP的降低可以预测唑来膦酸能有效控制非小细胞肺癌骨转移,反之,无应用唑来膦酸的价值。     

BSP和PTHrP的联合检测对乳腺癌骨转移临床意义的研究

目的:探讨骨唾液蛋白(BSP)和甲状旁腺相关蛋白(PTHrP)的联合检测对乳腺癌骨转移的临床意义.方法:乳腺癌87例患者,分为骨转移组40例和无骨转移组47例.应用免疫组织化学法检测石蜡包埋标本BSP和PTHrP的表达.结果:BSP和PTHrP在骨转移组的阳性表达均明显高于无骨转移组(x2值分别为8.47和10.49,P均<0.01),且强阳性表达也均高于后者(x2值分别为9.18和11.05,P均<0.05);同时两者在骨转移组的阳性表达与无转移组和骨外转移组之间比较,差异有统计学意义(P<0.01),而后两组间阳性表达差异无统计学意义(P>0.05).Cox比例风险回归模型分析结果发现,乳腺癌组织中BSP和PTHrP的高表达是预测骨转移的主要危险因素(P<0.01),其相对危险度分别为1.293和1.348.Log-rank生存曲线分析结果显示,在乳腺癌患者中BSP和PTHrP高表达者的累积生存概率均明显低于BSP和PTHrP阴性表达组,P<0.05.结论:BSP和PTHrP的过表达是早期预测乳腺癌骨转移的良好标志,并可作为评估乳腺患者的一项重要的预后因子.     

血清TRACP5b、CA15-3水平预测乳腺癌术后骨转移的临床意义

研究表明,乳腺癌骨转移中10%为成骨型,10%为混合型,80%均为以破骨细胞活动为主的溶骨性转移,而血清抗酒石酸盐酸性磷酸酶5b(Serum tartrate resistant acid phosphatase,TRACP5b)主要来源于破骨细胞,是一个反映破骨细胞功能的指标[1],故在众多乳腺癌骨转移标志物中显示出很高的特异性.肿瘤相关抗原15-3(Cancer antigen15-3,CA15-3)为乳腺癌相关抗原,被认为是一种相关性较高的乳腺癌标志物.文献报道,CA15-3在两处及两处以上骨转移灵敏性为100%;同时其值大于100U/ml时,应高度怀疑骨转移[2].本研究乳腺癌术后骨转移患者血清TRACP5b及CA15-3水平,旨在探讨早期预测乳腺癌术后骨转移的良好标志物,从而指导临床及早发现患者骨转移倾向,做到早发现,早治疗,提高患者的生存期和生活质量.     

血清Tracp5b诊断乳腺癌骨转移及评价双膦酸盐治疗疗效的临床意义

目的：比较乳腺癌患者血清抗酒石酸酸性膦酸酶（Tracp5b）、糖类抗原-153（CA-153）及癌胚抗原（CEA）在诊断乳腺癌骨转移及评价双膦酸盐治疗效果中的临床意义。方法：采用酶联免疫吸附法（ELISA）及电化学发光法检测18名健康女性、26例无骨转移乳腺癌患者及32例乳腺癌骨转移患者的血清Tracp5b、CA-153及CEA水平;检测其中19例乳腺癌骨转移患者口服双膦酸盐骨膦（氯膦酸二钠）治疗3个月后血清Tracp5b、CA-153和CEA水平。结果：乳腺癌骨转移组血清Tracp5b的水平较无骨转移组及健康对照组明显升高,差异有统计学意义,P〈0．05;血清Tracp5b诊断乳腺癌骨转移的敏感性为78．13％,特异性为86．36％;CA-153敏感性为37．50％,特异性为77．27％;CEA敏感性为21．88％,特异性为84．09％;Tracp5b的敏感性较CA-153、CEA高,差异有统计学意义,P〈0．05。骨转移组19例患者经双膦酸盐治疗3个月后Tracp5b水平明显下降,差异有统计学意义（P〈0．05）,而CA-153及CEA下降不明显,差异无统计学意义,P〉0．05。结论：Tracp5b在诊断乳腺癌骨转移中的敏感性较CA-153、CEA为高,可作为诊断乳腺癌骨转移和评价双膦酸盐治疗疗效血清标志之一。     

血清Tracp5b在乳腺癌骨转移诊断和治疗效果监测方面的临床价值

目的:探讨血清抗酒石酸酸性磷酸酶5b(tartrate-resistant acid phosphatase 5b,Tracp5b)在诊断乳腺癌骨转移以及评价乳腺癌骨转移治疗效果方面的价值.方法:采用酶联免疫吸附法(enzyme-linked immumosorbent assay,ELISA)检测30例无骨转移乳腺癌患者及22例乳腺癌骨转移患者的血清Tracp5b水平,并检测骨转移患者应用化疗或内分泌治疗同时加用双膦酸盐治疗4个月后血清Tracp5b水平,对检测结果的差异性进行比较.结果:相对于乳腺癌无骨转移组,骨转移组血清Tracp5b的水平明显升高,差异有统计学意义(P＜0.05);在化疗或内分泌治疗同时加用双膦酸盐治疗4个月后,骨转移组患者的血清Tracp5b水平明显下降,差异有统计学意义(P＜0.05).结论:血清Tracp5b在发生乳腺癌骨转移时明显升高,在治疗显效后显著下降,Tracp5b可作为诊断乳腺癌骨转移和评价乳腺癌骨转移治疗效果的血清学指标.     

MMP-9、BSP与LRP在乳腺癌组织中表达的研究

目的：探讨基质金属蛋白酶-9（MMP-9）、骨唾液蛋白（BSP）与肺耐药蛋白（LRP）在正常乳腺组织及乳腺癌组织中的表达状况。方法：应用免疫组化SP法检测60例正常乳腺组织及60例乳腺癌组织中MMP-9、BSP与LRP的表达。结果：乳腺癌组织中MMP-9、BSP与LRP 的阳性表达率分别为75.0％、78.3％、68.3％。正常乳腺组织中MMP-9、BSP与LRP的阳性表达率分别为21.7％、15.0％、10.0％。二者的差异有显著的统计学意义（ P＜0.05）。乳腺癌组织中MMP-9、BSP与LRP的表达呈正相关。结论：MMP-9、BSP与LRP在乳腺癌组织中高表达,与乳腺癌的浸润和转移相关。     

Tartrate-resistant acid phosphatase 5b activity is a useful bone marker for monitoring bone metastases in breast cancer patients after treatment.

Metabolic markers of bone metabolism may be useful for the diagnosis and monitoring of bone metastasis in breast cancer patients. Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity is a novel bone resorption marker. The treatment response of serum TRACP5b activity, bone alkaline phosphatase (BAP) activity, and concentrations of NH(2)-terminal telopeptide of type 1 collagen (NTX) in 68 breast cancer patients with bone metastasis were determined. These patients were treated and followed up as clinically indicated. Fifty-four healthy women were recruited as control. Serum TRACP5b activity, BAP activity, and NTX level of breast cancer patients with bone metastasis were significantly higher than those of normal controls. In normal subjects, serum TRACP5b activity and NTX level are significantly correlated (P < 0.0001). Neither was correlated with BAP activity. In breast cancer patients with bone metastasis, all marker pairs correlated to each other significantly (P < 0.0001). Biomarkers were examined repeatedly in 38 patients who were evaluable for treatment response. Based on clinical criteria, 20 patients were responders and 18 were nonresponders. In the 20 responders, serum TRACP5b activity and NTX level decreased significantly (P < 0.0001 and 0.0107, respectively) after treatment. In the 18 nonresponders, only NTX level showed significant increase (P = 0.0342) after treatment; TRACP5b and BAP were unchanged. By means of multiple logistic regression with stepwise selection, we determined that TRACP5b activity has a higher probability than NTX level to indicate treatment response as a function of percent change after treatment (18 times versus 12 times). Our data support the use of either TRACP5b activity or NTX level to follow up breast cancer patients with bone metastasis after treatment instead of the prevailing BAP activity.     

Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis.

Bone sialoprotein (BSP) is a noncoflagenous bone matrix protein that is important for both mineralization and cell-cell interactions. Tissue studies in primary breast cancers have shown that immunohistochemical expression of BSP is associated with a high incidence of bone metastases in the course of the disease. We used a RIA to investigate the importance of serum BSP as a marker for subsequent bone metastases. Between 1994 and 1996, preoperative blood samples were collected from 388 consecutive patients with nonmetastatic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA. The cutoff for elevated serum BSP values was 24 ng/ml, ie., two SDs above the normal mean value. Serum BSP was correlated with the risk of metastasis and analyzed with regard to its prognostic value. After a median follow-up period of only 20 months, 28 patients had developed metastases. Fourteen patients had bone metastases only, 9 visceral metastases only, and 5 a combination of osseous and visceral metastases. Of the 19 women with skeletal metastases, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP values: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for combined metastases), whereas none of the women with visceral metastases only had elevated serum BSP concentrations (median BSP value: 12.3 ng/ml). The median serum BSP value in the control group (benign breast disease) was 8.8 ng/ml serum BSP; levels correlated with the size of the primary tumor, but not with any other prognostic factors. Using a multivariate regression analysis, serum BSP was found to be the most important independent prognostic factor for the development of skeletal metastasis (P < 0.001; relative risk, 94); its specificity was 96.7%, and its sensitivity was 89.5%. Our study shows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surgery. The mechanism of BSP in the pathogenesis of skeletal metastases is unclear. Because BSP contains an integrin recognition sequence, its expression in tumor cells may facilitate their adhesion to the bone surface. However, it is possible that a proportion of circulation BSP is derived from normal or tumor-induced bone turnover. Breast cancer patients with elevated serum BSP levels may benefit from osteoprotective adjuvant therapy with bisphosphonates.     

Serum tartrate-resistant acid phosphatase 5b activity as a prognostic marker of survival in breast cancer with bone metastasis

Background  

Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) activity is a marker of osteoclast number and is elevated in breast cancer (BC) patients with extensive bone metastasis, which might in turn reflect the tumour burden. We tested the hypothesis that baseline serum TRACP 5b activity and its interval change are potential prognostic markers of survival in BC patients with bone metastasis.     

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.     

血清BSP水平联合PSADT检测在前列腺癌骨转移早期诊断中的价值

目的探讨骨代谢生化指标骨唾液酸蛋白 ( bone sialoprotein,BSP ) 联合前列腺特异性抗原倍增时间(prostate-specific antigen doubling time,PSADT)检测在前列腺癌骨转移临床诊断中的意义。方法选择 2009年1月-2011年4月我院收治的前列腺癌患者58例,依据诊断分为转移组（28例）和无骨转移组（30例）,取前列腺良性增生患者60例以及60例健康体检人员分别作为增生组和健康对照组。采用视觉模拟疼痛评分( VAS)评价骨痛程度;采用ELISA法检测血清BSP水平;采用电化学免疫发光技术检测血清f-PSA、t-PSA水平,采用倍增公式PSADT=lg(2) [log(PSA2)-log(PSA1)]计算PSADT;采用ROC曲线评价BSP、PSADT及两者联合检测在前列腺癌骨转移诊断中的意义。结果两组患者BSP水平均高于健康对照组和增生组(P<0.05);骨转移组患者血清BSP水平均明显高于无转移组(P<0.05);Pearson’s分析结果显示：前列腺癌骨转移患者的BSP和VAS骨痛评分呈显著正相关（P<0.05）;ROC曲线显示, BSP 诊断骨转移的敏感度和特异性分别为71.12%和72.8%;PSADT诊断骨转移的敏感度和特异性分别为84.15%和82.96%;BSP联合PSADT在前列腺癌骨转移诊断中的敏感度、特异性、AUC面积分别为91.26%,89.54%,0.932。结论BSP可能是前列腺癌骨转移患者的有效诊断指标;BSP和PSADT联合检测能大大提高前列腺癌骨转移的敏感度和准确性,便于前列腺癌骨转移的早期诊断。     

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation

Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BM-), 28 patients with breast carcinoma and BM (BC/BM+) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFbeta1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b (+95%, P=0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P=0.006), MMP-7 (P=0.004) and TIMP-1 (P=0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients.     

Bone sialoprotein‐αvβ3 integrin axis promotes breast cancer metastasis to the bone

The underlying mechanisms of breast cancer cells metastasizing to distant sites are complex and multifactorial. Bone sialoprotein (BSP) and αvβ3 integrin were reported to promote the metastatic progress of breast cancer cells, particularly metastasis to bone. Most theories presume that BSP promotes breast cancer metastasis by binding to αvβ3 integrin. Interestingly, we found the αvβ3 integrin decreased in BSP silenced cells (BSPi), which have weak ability to form bone metastases. However, the relevance of their expression in primary tumor and the way they participate in metastasis are not clear. In this study, we evaluated the relationship between BSP, αvβ3 integrin levels, and the bone metastatic ability of breast cancer cells in patient tissues, and the data indicated that the αvβ3 integrin level is closely correlated to BSP level and metastatic potential. Overexpression of αvβ3 integrin in cancer cells could reverse the effect of BSPi in vitro and promote bone metastasis in a mouse model, whereas knockdown of αvβ3 integrin have effects just like BSPi. Moreover, The Cancer Genome Atlas data and RT‐PCR analysis have also shown that SPP1, KCNK2, and PTK2B might be involved in this process. Thus, we propose that αvβ3 integrin is one of the downstream factors regulated by BSP in the breast cancer‐bone metastatic cascade.     

Clinical evaluation of serum osteocalcin in patients with bone metastasis of breast cancer

Bone metastasis is one of the characteristic behavior of recurrent breast cancer. Usually, X-ray detect and/or bone scintigraphy are used to evaluate bone metastasis. However, false positive cases are occasionally encountered in these modalities. This is a report of the results from the measurement of serum osteocalcin (OC) in breast cancer with bone metastasis. OC is one of the protein dependent on Vitamin K. The results were as follows: 1) Serum levels of OC in 56 patients with primary breast cancer were measured. The mean level of serum OC was significantly higher than that in patients with benign breast disease. But the comparisons in each stage were not statistically significant. 2) The mean serum OC level in patients of primary breast cancer with bone metastasis was higher than that in breast cancer without bone metastasis (p less than 0.05). This was remarkable in the patients of recurrent breast cancer (p less than 0.01). 3) Serum OC levels in bone metastasis patients were increased in group with normocalcemia, while it was normal or decreased in that with hypercalcemia. There was no significant correlation between either serum OC and ALP values, or between serum OC and serum Ca values. The slight positive and reverse correlation were observed between OC and ALP, OC and sCa, respectively. 4) In many cases with bone metastasis, serum OC levels were elevated before bone lesions were detected by bone scintigraphy. 5) In advanced stage of the patients with bone metastasis and hypercalcemia, serum OC level decreased. The increased level of serum OC was maintained when high dose of calcitonin was administered.