乳腺癌微钙化的病理归类分析及傅里叶变换红外光谱研究
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摘要
乳腺癌微钙化作为乳腺癌的重要特征已广泛用于临床乳腺癌的早期诊断中,但目前其产生机制尚不明确,将其应用于乳腺癌的临床诊断之中其理论依据尚不充分。傅里叶红外光谱作为分析物质组成和结构特点方面的有效工具具有操作简便、分辨率高、重复性好的特点,已大量应用于各研究领域之中。本论文通过分析临床乳腺癌微钙化病例HE切片下的病理特征,对乳腺癌微钙化进行病理学归类分析,及利用傅里叶红外光谱显微镜分析乳腺癌微钙化病例中的微钙化灶的红外光谱特征,得到乳腺癌微钙化灶3层结构的组成特点及相互关系,从而进一步推测乳腺癌微钙化可能的产生机制。
本博上论文以乳腺癌微钙化病例为研究对象,开展了如下工作：1.通过分析临床乳腺癌微钙化病例HE切片下的病理特征,对乳腺癌微钙化进行病理学归类分析；2.建立用傅里叶红外光谱测量乳腺癌微钙化灶的模型；3.利用傅里叶变换红外光谱分析乳腺癌微钙化病例的钙化灶、钙化周围坏死灶、钙化周围癌组织红外光谱之间的关系。本论文取得了一下主要结果：
1.140乳腺癌病例的微钙化病理归类分析：通过判断钙化灶是否在管腔内,是否伴凝固性性坏死,可将浸润性导管癌微钙化病例分为3类：Ⅰ a型、管腔内伴凝固性坏死型,Ⅰ b型、管腔内无坏死型,Ⅱ型、管腔外钙化型,70%的浸润性导管癌癌微钙化属于Ⅰ A型,20%属于Ⅰ B型,10%属于Ⅱ型(p<0.01);140例浸润性导管癌微钙化病例中,51%(72例)全部为浸润癌,49%(68例)的病例含有DCIS成分,68例含有DCIS成分的钙化病例100%(68例)属于管腔内型。
2.建立用傅里叶红外光谱测量乳腺癌微钙化灶的模型：经统计学分析,钙化区(A区)、坏死区(B区)、钙化周围癌组织区(C区)几个基本特征峰的峰位基本相同,表明3个区所含物质的基团基本一致,主要是细胞内蛋白质、核酸和CHAP的吸收信号。通过峰高和峰面积的对比,钙化周围癌组织区(C区)酰胺各谱带的峰强度均大于其他两个区,组问差异具有统计学意义,故傅里叶变换红外光谱应用于乳腺癌微钙化研究是可行的。
3.在30例乳腺癌微钙化病例中,96.7%的病例钙化区、坏死区和钙化周围癌组织区所含主要成分相同,为蛋白质和含碳羟基磷灰石(CHAP),钙化周围癌组织区含蛋白质成分最高,其次为坏死区,钙化区含蛋白质成分最低(P<0.001),而CHAP在钙化周围癌组织区含量最低,其次为坏死区,钙化区含CHAP成分最高(P<0.001)。这表明乳腺癌细胞本身可以合成CHAP,而管腔中的CHAP很有可能在大量乳腺癌细胞死亡后堆积形成。研究中发现钙化区、坏死区和钙化周围癌组织区CHAP含量呈梯度下降，这可能和乳腺导管腔的特殊环境有密切关系。
上述研究结果表明：乳腺癌微钙化最初可能形成于乳腺导管周围的乳腺癌细胞,而导管腔内的钙化与乳腺导管周围的癌细胞及乳腺导管腔的特殊环境密切相关。这将为今后的乳腺癌微钙化形成机制研究提供依据,同时为乳腺癌微钙化用于乳腺癌的临床诊断提供理论依据,并将有利于将傅里叶红外光谱推广到乳腺癌的临床诊断和研究之中。
Calcifications are very important diagnosis information in breast tumor.Now we can distinguish between benign and malignant lesions by the analysis of calcifications.Recent reseach tells us,the characters of breast microcalcifications are maybe related to prognosis of patients.
The mechanism of breast microcalcification forming is not clear now. Calcifications have been known as deposition of tissue necrosis.In particular, the issue as to whether it is a sign of degeneration or of an active cell process is still unresolved. In earlier studies, breast tumors were shown to demonstrate both amorphous and crystalline deposits.
The infiltrating ductal carcinoma cases with breast microcalcifications were chosen as research obiects. The following work was carried out:1. we classify the infiltrating ductal carcinoma cases with breast microcalcifications by the the characters of pathology;2.we build the study model of breast microcalcifications by FTIR;3.we analyse the breast microcalcification focus,the necrosis around the microcalcifications and the tumor tissue around the microcalcifications by FTIR. The following main results were obtained:
1. The pathological classificasion analysis of140Infiltrating Ductal Carcinoma cases with breast microcalcifications:According to the microcalcifications in lumen or out of lumen,and the microcalcifications with coagulation necrosis or without coagulation necrosis,we classify the breast microcalcifications in infiltrating ductal carcinoma into three types:type I a are microcalcifications in lumen with coagulation necrosis,type I b are microcalcifications in lumen without coagulation necrosis,type Ⅱ is out of lumen.70%of cases are type I a,20%of cases are type I b,and10%of cases are type Ⅱ(p<0.01).51%of the cases are Invasive ductal carcinoma(without DCIS),while49%of cases are DCIS.100%of cases with DCIS are in lumen.
2. We build the study model of breast microcalcifications by FTIR:After statistical analysis, the calcified area (A), necrotic zone (B zone), calcified the cancer tissue around the area (C area) a few basic characteristics peak position is basically the same, indicating that the basic groups of substances contained in three districtsconsistent absorption signals of intracellular proteins, nucleic acids, and CHAP. Through the comparison of the peak height and peak area, the peak intensity of calcified the cancer tissue around the area (C area) amide bands are larger than the other two districts, a statistically significant difference between the two groups, so the Fourier transform infrared spectroscopy applied to breast cancer the microcalcifications research is feasible.
3.By Fourier transform infrared spectroscopy of breast cancer cases of microcalcifications calcification, calcification around necrosis, calcification around the cancer tissue between the infrared spectrum:found in breast microcalcifications, calcification, areas of necrosis and calcification aroundcancer tissue area contained the same basic ingredients, showed that the calcification area around the cancer cells have been CHAP ingredients for protein and CHAP, CHAP ingredients necrotic area, which showed that breast cancer cells can synthesize CHAP, the lumen CHAP is likely to be stacked to form after the death of a large number of breast cancer cells. The study found that calcification area, areas of necrosis and calcification around the cancerous tissue area CHAP content with a declining gradient, which may be closely related to the special environment and ductal breast cavity.
The results of the study show that:the breast microcalcifications initially formed around ductal breast cancer cells, the catheter lumen calcification breast ductal around cancer cells closely related. This will be the future of breast microcalcifications formation mechanism studies provide a basis to provide a theoretical basis for the clinical diagnosis of breast cancer as well as breast microcalcifications, Fourier transform infrared spectroscopy and will contribute to the promotion to the clinical diagnosis of breast cancer and study.
本博上论文以乳腺癌微钙化病例为研究对象,开展了如下工作：1.通过分析临床乳腺癌微钙化病例HE切片下的病理特征,对乳腺癌微钙化进行病理学归类分析；2.建立用傅里叶红外光谱测量乳腺癌微钙化灶的模型；3.利用傅里叶变换红外光谱分析乳腺癌微钙化病例的钙化灶、钙化周围坏死灶、钙化周围癌组织红外光谱之间的关系。本论文取得了一下主要结果：
1.140乳腺癌病例的微钙化病理归类分析：通过判断钙化灶是否在管腔内,是否伴凝固性性坏死,可将浸润性导管癌微钙化病例分为3类：Ⅰ a型、管腔内伴凝固性坏死型,Ⅰ b型、管腔内无坏死型,Ⅱ型、管腔外钙化型,70%的浸润性导管癌癌微钙化属于Ⅰ A型,20%属于Ⅰ B型,10%属于Ⅱ型(p<0.01);140例浸润性导管癌微钙化病例中,51%(72例)全部为浸润癌,49%(68例)的病例含有DCIS成分,68例含有DCIS成分的钙化病例100%(68例)属于管腔内型。
2.建立用傅里叶红外光谱测量乳腺癌微钙化灶的模型：经统计学分析,钙化区(A区)、坏死区(B区)、钙化周围癌组织区(C区)几个基本特征峰的峰位基本相同,表明3个区所含物质的基团基本一致,主要是细胞内蛋白质、核酸和CHAP的吸收信号。通过峰高和峰面积的对比,钙化周围癌组织区(C区)酰胺各谱带的峰强度均大于其他两个区,组问差异具有统计学意义,故傅里叶变换红外光谱应用于乳腺癌微钙化研究是可行的。
3.在30例乳腺癌微钙化病例中,96.7%的病例钙化区、坏死区和钙化周围癌组织区所含主要成分相同,为蛋白质和含碳羟基磷灰石(CHAP),钙化周围癌组织区含蛋白质成分最高,其次为坏死区,钙化区含蛋白质成分最低(P<0.001),而CHAP在钙化周围癌组织区含量最低,其次为坏死区,钙化区含CHAP成分最高(P<0.001)。这表明乳腺癌细胞本身可以合成CHAP,而管腔中的CHAP很有可能在大量乳腺癌细胞死亡后堆积形成。研究中发现钙化区、坏死区和钙化周围癌组织区CHAP含量呈梯度下降，这可能和乳腺导管腔的特殊环境有密切关系。
上述研究结果表明：乳腺癌微钙化最初可能形成于乳腺导管周围的乳腺癌细胞,而导管腔内的钙化与乳腺导管周围的癌细胞及乳腺导管腔的特殊环境密切相关。这将为今后的乳腺癌微钙化形成机制研究提供依据,同时为乳腺癌微钙化用于乳腺癌的临床诊断提供理论依据,并将有利于将傅里叶红外光谱推广到乳腺癌的临床诊断和研究之中。
Calcifications are very important diagnosis information in breast tumor.Now we can distinguish between benign and malignant lesions by the analysis of calcifications.Recent reseach tells us,the characters of breast microcalcifications are maybe related to prognosis of patients.
The mechanism of breast microcalcification forming is not clear now. Calcifications have been known as deposition of tissue necrosis.In particular, the issue as to whether it is a sign of degeneration or of an active cell process is still unresolved. In earlier studies, breast tumors were shown to demonstrate both amorphous and crystalline deposits.
The infiltrating ductal carcinoma cases with breast microcalcifications were chosen as research obiects. The following work was carried out:1. we classify the infiltrating ductal carcinoma cases with breast microcalcifications by the the characters of pathology;2.we build the study model of breast microcalcifications by FTIR;3.we analyse the breast microcalcification focus,the necrosis around the microcalcifications and the tumor tissue around the microcalcifications by FTIR. The following main results were obtained:
1. The pathological classificasion analysis of140Infiltrating Ductal Carcinoma cases with breast microcalcifications:According to the microcalcifications in lumen or out of lumen,and the microcalcifications with coagulation necrosis or without coagulation necrosis,we classify the breast microcalcifications in infiltrating ductal carcinoma into three types:type I a are microcalcifications in lumen with coagulation necrosis,type I b are microcalcifications in lumen without coagulation necrosis,type Ⅱ is out of lumen.70%of cases are type I a,20%of cases are type I b,and10%of cases are type Ⅱ(p<0.01).51%of the cases are Invasive ductal carcinoma(without DCIS),while49%of cases are DCIS.100%of cases with DCIS are in lumen.
2. We build the study model of breast microcalcifications by FTIR:After statistical analysis, the calcified area (A), necrotic zone (B zone), calcified the cancer tissue around the area (C area) a few basic characteristics peak position is basically the same, indicating that the basic groups of substances contained in three districtsconsistent absorption signals of intracellular proteins, nucleic acids, and CHAP. Through the comparison of the peak height and peak area, the peak intensity of calcified the cancer tissue around the area (C area) amide bands are larger than the other two districts, a statistically significant difference between the two groups, so the Fourier transform infrared spectroscopy applied to breast cancer the microcalcifications research is feasible.
3.By Fourier transform infrared spectroscopy of breast cancer cases of microcalcifications calcification, calcification around necrosis, calcification around the cancer tissue between the infrared spectrum:found in breast microcalcifications, calcification, areas of necrosis and calcification aroundcancer tissue area contained the same basic ingredients, showed that the calcification area around the cancer cells have been CHAP ingredients for protein and CHAP, CHAP ingredients necrotic area, which showed that breast cancer cells can synthesize CHAP, the lumen CHAP is likely to be stacked to form after the death of a large number of breast cancer cells. The study found that calcification area, areas of necrosis and calcification around the cancerous tissue area CHAP content with a declining gradient, which may be closely related to the special environment and ductal breast cavity.
The results of the study show that:the breast microcalcifications initially formed around ductal breast cancer cells, the catheter lumen calcification breast ductal around cancer cells closely related. This will be the future of breast microcalcifications formation mechanism studies provide a basis to provide a theoretical basis for the clinical diagnosis of breast cancer as well as breast microcalcifications, Fourier transform infrared spectroscopy and will contribute to the promotion to the clinical diagnosis of breast cancer and study.
引文
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[1]Castronovo V, Bellahccne A. Evidence that breast cancer associated microcalcifications are mineralized malignant cells. [J] Int J Cancer 1998;12:305 8.
[2]Holme T. Reis M, Thimpson A, Robertson A, Parham D, Hickman P. Preccc P. Is mammographic microcalcifiication of biological significance? [J]Eur J Surg Oncol 1993;19:250-3.
[3]Chen DR, Chien SY, Kuo S.I, Teng YH, Tsai HT, Kuo JH, Chung JG SLC34A2 as a novel marker for diagnosis and targeted therapy of breast cancer. [J]Anticancer Res 2010: 30: 4135-4140.
[4]Tabar L, Chen HH, Duffy SW, Yen MF, Chiang CF. Dean PB. Smith RA. A novel method for prediction of long-term outcome of women with T1a,T1b, and 10- 14mm invasive breast cancers: A prospective study.[J]Lancet 2000:355:429 - 33.
[5]Morgan MR, Cooke MM. McCarthy GM. Microcalcifications Associated with Breast Cancer: An Epiphcnomenon or Biologically Significant Feature of Selected Tumors? [J]J Mammary Gland Biol Neoplasia. 2005: 10(2): 181-7.
[6]Baker R, Rogers KD, Shepherd N. Stone N. New relationships between breast microcalcifications and cancer.[J]Br J Cancer.2010;103(7):1034-9.
|7] Ahmed A. Calcification in human breast carcinoma: ultrastructural observations. [J]J Pathol 1975:117:247-51.
[8]Liu F, Bloch N, Bhushan KR, De Grand AM, Tanaka E, Solazzo S. Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcification. [J] Mol Imaging 2008 ;7(4): 175-186.
[9]Bellahcene A, Mervillc M, Castronovo V. Expression of bone sialoprotein, a bone matrix protein, in human breast cancer. [J]Cancer Res 1994:54:2823 - 6.
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[11]Morgan M, Cooke M, Christopherson P, Westfall P, McCarthy G. Calcium hydroxyapatite promotes mitogencsis and matrix metalloproteinase expression in human breast cancer cell lines. [J] Mol Carcinog 2001;32:111-7.
[12]Liu F. Bloch N, Bhushan KR, De Grand AM, Tanaka E. Solazzo S. Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcification. [J]Mol Imaging. 2008;7(4): 175-186.
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[14]Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phospha-tase activity. [J] J Biol Chem.2007.282:15872-15883
[15]Cooke M, McCarthy M, Sallis J, Morgan M. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1, and cyclooxygenase-2 mRNA in human breast cancer cell lines. [J]Breast Cancer Res Treat 2003;79:253-63.
[16]Porter A, Patel N, Brooks R, Best S, Rushton N, Bonfield W. Effect of carbonate substitution on the ultrastructural characteristics of hydroxyapatite implants. [J]Journal of Materials Science:Materials in Medicine.2005; 16:899-907.
[17]Reuben PM, Brogley MA, Sun Y, Cheung HS. Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals-Role of calcium dependent protein kinase C alpha. [J] J Biol Chem 2002; 277:15190-8.
[18]Sun Y, Zeng XR, Wenger L, Cheung HS. Basic calcium phosphate crystals stimulate the endocytotic activity of cells-inhibition by anticalcification agents. [J]Biochemical and Biophysical Research Communications 2003; 312:1053-9.
[19]Cox RF, Hernandez-Santana A, Ramdass S, McMahon G, Harmey JH, Morgan MP. Microcalcifications in breast cancer:novel insights into the molecular mechanism and functional consequence of mammary mineralisation. [J] Br J Cancer 2012,106(3):525-537.
[20]Shroff RC, Shanahan CM. The vascular biology of calcification.. Semin Dial.2007.20: 103-109.
[21]McSherry EA, Brennan K, Hudson L, Hill AD, Hopkins AM. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rapl GTPase. Breast Cancer Res.2011.13:R31.
[22]Mansson E, Bergkvist L, Christenson G, Persson C, Warnberg F. Mammographic casting-type calcifications is not a prognostic factor in unifocal small invasive breast cancer:a population-based retrospective cohort study. J Surg Oncol.2011.100:670-674.
[23]Reuben PM, Brogley MA, Sun Y, Cheung HS. Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals-Role of calcium dependent protein kinase Calpha. [J]J Biol Chem 2002; 277:15190-8.
[24]Sun Y, Zeng XR, Wenger L, Cheung HS. Basic calcium phosphate crystals stimulate the endocytotic activity of cells-inhibition by anticalcification agents. [J] Biochemical and Biophysical Research Communications 2003:312:1053-9.
[25]Maziak DE, Do MT, Shamji FM, Sundaresan SR, Perkins DG, Wong PTT. Fourier-transform infrared spectroscopic study of characteristic molecular structure in cancer cells of esophagus: An exploratory study [J]. Cancer Detect. Prev.2007:31:244-253.
[26]张莉，王健生,杨展澜,徐抬庄,翁诗甫，石景森,吴谨光.正常与癌症肺组织的傅里叶变换红外光谱差异的研究[J].高等学校化学学报,2003.24(12)：2173-2176.
[27]Kuimova MK, Chan KLA,Kazarian SG. Chemical imaging of live cancer cells in the natural aqueous environment. Appl. Spectrosc.2009;63:164-171.
[28]王旭明.近年来红外光谱在临床医药学中的应用新近展[J].现代代仪器,2007.1：5-9.
[29]Hart, S Avramidis, S Mansfield. Detection of wet-pockets in hemlock using, near Spectroscopy[C]. Conference COST,2008; E53,29-30.
[30]S.C. Whiteman, Y. Yang, J.M. Jones, et al. FTIR spectroscopic analysis of sputum: Preliminary findings on a potential novel diagnostic marker for COPD[J].Ther Adv Resnir Dis; 2008:2(11:23-31.
[31]Miller LM, Smith GD, Carr GL. Synchrotron-based biological micro- -spectroscopy from the mid-infrared through the Far-infrared regimes [J]. J. Biol. Phys.,2003;29:219-230.
[32]马晓冬.傅立叶变换红外光谱在癌症检测中的应用研究：[硕士].2007.合肥：中国科学技术大学.
[33]Benjamin Bird, Milos Miljkovic, Melissa J Romeo, et al.micro-spectral imaging:distinction of tissue types in axillary node histology[J].Clinical Pathology,2008:8:8-21.
[34]高体玉,慈云祥,李峻.肿瘤的红外光谱分析研究进展[J].2000.化学建展,12(3)：346-353.
[35]A, Barth, P.I. Hans (Eds.), Advances in Biomedical Spectroscopy, volume 2:Biological and Biomedical Infrared Spectroscopy, IOS press,2009, p.133.
[36]Gazi E, Dwyer J. Lockyer NP, Miyan J, Gardner P, Hart CA, Brown MD, Clarke NW.2005. A study of cytokinetic and motile prostate cancer cells using synchrotron-based FTIR microspecrtoscopic imaging [J]. Vibrational Spectroscopy 38:193-201.
[37]Dumas P, Sockalingum GD, Sule-suso J.2007. Adding synchrotron radiation to infrared microspectroscopy:what's new in biomedical applications? [J]. Trends. BiotechnoL,25:40-44.
[38]Liu MJ, Wang Z, Wu RC,Sun SQ, Wu QY_ 2003. Monitoring all-transretinoic acid-induced differentiation of human acute promyelocytic leukemia NB4 cells by Fourier-transform infrared spectroscopy [J]. Leukemia,17:1670-1674.
[39]Wang X, Qi ZM, Liu XC, Wang SY, Li CX, Liu G, Xiong Y, Li TT, Tao JQ, Tian YC. 2010.The comparison of hair from gastric cancer patients and from healthy persons studied by infrared microspectroscopy and imaging using synchrotron radiation [J], Cancer. Epidemiol.,34: 453-456.
[40]Cai SW, Singh BR.1999. Identification of P-turn and random coil amide III infrared bands for secondary structure estimation of proteins [J]. Biophys. Chem.80:7-20.
[41]Chen YJ, Cheng YD, Liu HY, Lin PY, Wang CS.2006. Observation of biochemical imaging changes in human pancreatic cancer tissue using Fourier-transform infrared microspectroscopy [J]. Chang Gung. Med. J.,29:518-27.
[2]Castronovo V,Bellahcene A.Evidence that breast cancer associated microcalcifications are mineralized malignant cells[J].Int J Cancer 1998,12:305-8.
[3]Langen H-J,Koehler S,Bielmeier J,et al.Microradiography of microcalcifications in breast specimen:a new histological correlation procedure and the effect of improved resolution on diagnostic validity[J].Radiol Res Pract 2012,2012:526293.
[4]Tse GM, Tan P-H, Cheung HS, et al. Intermediate to highly suspicious calcification in breast lesions:a radio-pathologic correlation [J]. Breast Cancer Res Treat,2007,110(1):1-7.
[5]Liu F, Bloch N, Bhushan KR, et al. Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcification[J]. Mol Imaging 2008,7(4):175-186.
[6]R F Cox, A Hernandez-Santana, S Ramdass,et al.Microcalcifications in breast cancer:novel insights into the molecular mechanism and functional consequence of mammary mineralisation[J].Br J Cancer 2012,106:525-537.
[7]Baker R,Rogers K D,Shepherd N,et al.New relationships between breast microcalcifications and cancer[J].Br J Cancer 2010 Sep 28,103(7):1034-9.
[8]Dillon Mary F,Maguire, Aoife A,McDermott Enda W,et al.Needle core biopsy characteristics identify patients at risk of compromised margins in breast conservation surgery[J].Mod Pathol. 2008Jan,21(1):39-45.
[9]Castronovo V, Bellahcene A. Evidence that breast cancer associated microcalcifications are mineralized malignant cells. Int J Cancer 1998; 12:305-8.
[10]Holme T, Reis M, Thimpson A, Robertson A, Parham D, Hickman P, Preece P. Is mammographic microcalcifiication of biological significance? [J] Eur J Surg Oncol 1993;19:250-3.
[11]Tabar L, Chen HH, Duffy SW, Yen MF, Chiang CF, Dean PB, Smith RA. A novel method for prediction of long-term outcome of women with Tla, T1b, and 10-14 mm invasive breast cancers:A prospective study. [J]Lancet 2000;355:429-33.
[12]Morgan MP, Cooke MM, McCarthy GM. Microcalcifications Associated with Breast Cancer: An Epiphenomenon or Biologically Significant Feature of Selected Tumors? [J] J Mammary Gland Biol Neoplasia.2005; 10(2):181-7.
[13]Liu F, Bloch N, Bhushan KR. De Grand AM,Tanaka E, Solazzo S.Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcitlcation.[J]Mol Imaging.2008;7(4):175-186.
[14]Morgan M, Cooke M, Christopherson P, Westfall P, McCarthy G. Calcium hydroxyapatite promotes mitogenesis and matrix metalloproteinase expression in human breast cancer cell lines. [J]Mol Carcinog 2001:32:111-7.
[15]Cooke M, McCarthy M, Sallis J, Morgan M. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1, and cyclooxygenase-2 mRNA in human breast cancer cell lines. [J] Breast Cancer Res Treat 2003;79:253-63.
[16]Porter A, Patel N. Brooks R, Best S, Rushton N, Bonfield W. Effect of carbonate substitution on the ultrastructural characteristics of hydroxyapatite implants. [J]Journal of Materials Science:Materials in Medicine.2005:16:899-907.
[17]Reuben PM, Brogley MA, Sun Y, Cheung HS. Molecular mechanism of the induction of metalloproteinases I and 3 in human fibroblasts by basic calcium phosphate crystals-Role of calcium dependent protein kinase Calpha. [J]J Biol Chem 2002:277:15190-8.
[18]Sun Y, Zeng XR, Wenger L, Cheung HS. Basic calcium phosphate crystals stimulate the endocytotic activity of cells-inhibition by anticalcification agents.[J] Biochemical and Biophysical Research Communications 2003; 312:1053-9.
[19]Maziak DE, Do MT, Shamji FM, Sundaresan SR. Perkins DG,Wong PTT. Fourier-transform infrared spectroscopic study of characteristic molecular structure in cancer cells of esophagus: An exploratory study [J]. Cancer Detect. Prev.2007;31:244-253.
[20]张莉,王健生，杨展澜，徐抬庄，翁诗甫，石景森,吴谨光.正常与癌症肺组织的傅里叶变换红外光谱差异的研究[J].高等学校化学学报，2003，24(12)：2173-2176.
[21]Kuimova MK. Chan KLA, Kazarian SG. Chemicalimaging of live cancer cells in the natural aqueous environment. Appl. Spectrosc.2009;63:164-171.
[22]王旭明.近年来红外光谱在临床医药学中的应用新进展[J].现代仪器，2007.1：5-9.
[23]Hart, S Avramidis, S Mansfield. Detection of wet-pockets in hemlock using, near Spectroscopy[C]. Conference COST,2008; E53,29-30.
[24]S.C. Whiteman, Y. Yang,J.M. Jones, et al. FTIR spectroscopic analysis of sputum: Preliminary findings on a potential novel diagnostic marker for COPD[J].Ther Adv Resnir Dis; 2008;2(11:23-31.
[25]Miller LM, Smith GD, Carr GL. Synchrotron-based biological micro--spectroscopy from the mid-infrared through the Far-infrared regimes [J]. J. Biol. Phys.,2003;29:219-230.
[26]马晓冬.傅立叶变换红外光谱在癌症检测中的应用研究：[硕士].2007.合肥：中国科学技术大学.
[27]Benjamin Bird, Milos Miljkovic, Melissa J Romeo, et al.micro-spectral imaging:distinction of tissue types in axillary node histology[J].Clinical Pathology,2008;8:8-21.
[28]高体玉,慈云祥,李峻.肿瘤的红外光谱分析研究进展[J].2000.化学进展,12(3)：346-353.
[29]A, Barth, P.I. Hans (Eds.), Advances in Biomedical Spectroscopy, volume 2:Biological and Biomedical Infrared Spectroscopy, IOS press,2009, p.133.
[30]Gazi E, Dwyer J, Lockyer NP, Miyan J, Gardner P, Hart CA, Brown MD, Clarke NW.2005. A study of cytokinetic and motile prostate cancer cells using synchrotron -based FTIR microspecrtoscopic imaging [J]. Vibrational Spectroscopy 38:193-201.
[31]Dumas P, Sockalingum GD, Sule-suso J.2007. Adding synchrotron radiation to infrared microspectroscopy:what's new in biomedical applications? [J]. Trends. BiotechnoL,25:40-44.
[32]Liu MJ, Wang Z, Wu RC, Sun SQ, Wu QY_ 2003. Monitoring all-transretinoic acid-induced differentiation of human acute promyelocytic leukemia NB4 cells by Fourier-transform infrared spectroscopy [J]. Leukemia,17:1670-1674.
[33]Wang X, Qi ZM, Liu XC, Wang SY, Li CX, Liu G, Xiong Y, Li TT, Tao JQ, Tian YC. 2010.The comparison of hair from gastric cancer patients and from healthy persons studied by infrared microspectroscopy and imaging using synchrotron radiation [J], Cancer. Epidemiol.,34: 453-456.
[34]Cai SW, Singh BR.1999. Identification of P-turn and random coil amide Ⅲ infrared bands for secondary structure estimation of proteins [J]. Biophys. Chem.80:7-20.
[35]Chen YJ, Cheng YD, Liu HY, Lin PY, Wang CS.2006. Observation of biochemical imaging changes in human pancreatic cancer tissue using Fourier-transform infrared microspectroscopy [J]. Chang Gung.Med.J.,29:518-27.
[36]Cooke M, McCarthy M,Sallis J, Morgan M. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and uprcgulation of matrix metalloproteinasc-1, inlcrleukin-1,and cvclooxygenase-2 mRNA in human breast cancer cell lines. [J]Breast Cancer Res Trent 2003;79:253 -63.
[1]Castronovo V, Bellahccne A. Evidence that breast cancer associated microcalcifications are mineralized malignant cells. [J] Int J Cancer 1998;12:305 8.
[2]Holme T. Reis M, Thimpson A, Robertson A, Parham D, Hickman P. Preccc P. Is mammographic microcalcifiication of biological significance? [J]Eur J Surg Oncol 1993;19:250-3.
[3]Chen DR, Chien SY, Kuo S.I, Teng YH, Tsai HT, Kuo JH, Chung JG SLC34A2 as a novel marker for diagnosis and targeted therapy of breast cancer. [J]Anticancer Res 2010: 30: 4135-4140.
[4]Tabar L, Chen HH, Duffy SW, Yen MF, Chiang CF. Dean PB. Smith RA. A novel method for prediction of long-term outcome of women with T1a,T1b, and 10- 14mm invasive breast cancers: A prospective study.[J]Lancet 2000:355:429 - 33.
[5]Morgan MR, Cooke MM. McCarthy GM. Microcalcifications Associated with Breast Cancer: An Epiphcnomenon or Biologically Significant Feature of Selected Tumors? [J]J Mammary Gland Biol Neoplasia. 2005: 10(2): 181-7.
[6]Baker R, Rogers KD, Shepherd N. Stone N. New relationships between breast microcalcifications and cancer.[J]Br J Cancer.2010;103(7):1034-9.
|7] Ahmed A. Calcification in human breast carcinoma: ultrastructural observations. [J]J Pathol 1975:117:247-51.
[8]Liu F, Bloch N, Bhushan KR, De Grand AM, Tanaka E, Solazzo S. Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcification. [J] Mol Imaging 2008 ;7(4): 175-186.
[9]Bellahcene A, Mervillc M, Castronovo V. Expression of bone sialoprotein, a bone matrix protein, in human breast cancer. [J]Cancer Res 1994:54:2823 - 6.
[10]Liu,F., P. Misra. et al. "A dose- and time-controllable syngeneic animal model of breast cancer microcalcification.". [J] Breast Cancer Res Treat.2008 .122(1): 87-94.
[11]Morgan M, Cooke M, Christopherson P, Westfall P, McCarthy G. Calcium hydroxyapatite promotes mitogencsis and matrix metalloproteinase expression in human breast cancer cell lines. [J] Mol Carcinog 2001;32:111-7.
[12]Liu F. Bloch N, Bhushan KR, De Grand AM, Tanaka E. Solazzo S. Humoral BMP-2 is Sufficient for Inducing Breast Cancer Microcalcification. [J]Mol Imaging. 2008;7(4): 175-186.
[13]Abigail S. Haka,2 Karen E. Shafer-Peltier,3 Maryann Fitzmaurice, Joseph Crowe, Ramachandra R. Dasari, and Michael S. Feld Identifying Microcalcifications in Benign and Malignant Breast Lesions by Probing Differences in Their Chemical Composition Using Raman Spectroscopy.[J] Cancer Res.2002.62,5375-5380, September 15.
[14]Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phospha-tase activity. [J] J Biol Chem.2007.282:15872-15883
[15]Cooke M, McCarthy M, Sallis J, Morgan M. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1, and cyclooxygenase-2 mRNA in human breast cancer cell lines. [J]Breast Cancer Res Treat 2003;79:253-63.
[16]Porter A, Patel N, Brooks R, Best S, Rushton N, Bonfield W. Effect of carbonate substitution on the ultrastructural characteristics of hydroxyapatite implants. [J]Journal of Materials Science:Materials in Medicine.2005; 16:899-907.
[17]Reuben PM, Brogley MA, Sun Y, Cheung HS. Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals-Role of calcium dependent protein kinase C alpha. [J] J Biol Chem 2002; 277:15190-8.
[18]Sun Y, Zeng XR, Wenger L, Cheung HS. Basic calcium phosphate crystals stimulate the endocytotic activity of cells-inhibition by anticalcification agents. [J]Biochemical and Biophysical Research Communications 2003; 312:1053-9.
[19]Cox RF, Hernandez-Santana A, Ramdass S, McMahon G, Harmey JH, Morgan MP. Microcalcifications in breast cancer:novel insights into the molecular mechanism and functional consequence of mammary mineralisation. [J] Br J Cancer 2012,106(3):525-537.
[20]Shroff RC, Shanahan CM. The vascular biology of calcification.. Semin Dial.2007.20: 103-109.
[21]McSherry EA, Brennan K, Hudson L, Hill AD, Hopkins AM. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rapl GTPase. Breast Cancer Res.2011.13:R31.
[22]Mansson E, Bergkvist L, Christenson G, Persson C, Warnberg F. Mammographic casting-type calcifications is not a prognostic factor in unifocal small invasive breast cancer:a population-based retrospective cohort study. J Surg Oncol.2011.100:670-674.
[23]Reuben PM, Brogley MA, Sun Y, Cheung HS. Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals-Role of calcium dependent protein kinase Calpha. [J]J Biol Chem 2002; 277:15190-8.
[24]Sun Y, Zeng XR, Wenger L, Cheung HS. Basic calcium phosphate crystals stimulate the endocytotic activity of cells-inhibition by anticalcification agents. [J] Biochemical and Biophysical Research Communications 2003:312:1053-9.
[25]Maziak DE, Do MT, Shamji FM, Sundaresan SR, Perkins DG, Wong PTT. Fourier-transform infrared spectroscopic study of characteristic molecular structure in cancer cells of esophagus: An exploratory study [J]. Cancer Detect. Prev.2007:31:244-253.
[26]张莉，王健生,杨展澜,徐抬庄,翁诗甫，石景森,吴谨光.正常与癌症肺组织的傅里叶变换红外光谱差异的研究[J].高等学校化学学报,2003.24(12)：2173-2176.
[27]Kuimova MK, Chan KLA,Kazarian SG. Chemical imaging of live cancer cells in the natural aqueous environment. Appl. Spectrosc.2009;63:164-171.
[28]王旭明.近年来红外光谱在临床医药学中的应用新近展[J].现代代仪器,2007.1：5-9.
[29]Hart, S Avramidis, S Mansfield. Detection of wet-pockets in hemlock using, near Spectroscopy[C]. Conference COST,2008; E53,29-30.
[30]S.C. Whiteman, Y. Yang, J.M. Jones, et al. FTIR spectroscopic analysis of sputum: Preliminary findings on a potential novel diagnostic marker for COPD[J].Ther Adv Resnir Dis; 2008:2(11:23-31.
[31]Miller LM, Smith GD, Carr GL. Synchrotron-based biological micro- -spectroscopy from the mid-infrared through the Far-infrared regimes [J]. J. Biol. Phys.,2003;29:219-230.
[32]马晓冬.傅立叶变换红外光谱在癌症检测中的应用研究：[硕士].2007.合肥：中国科学技术大学.
[33]Benjamin Bird, Milos Miljkovic, Melissa J Romeo, et al.micro-spectral imaging:distinction of tissue types in axillary node histology[J].Clinical Pathology,2008:8:8-21.
[34]高体玉,慈云祥,李峻.肿瘤的红外光谱分析研究进展[J].2000.化学建展,12(3)：346-353.
[35]A, Barth, P.I. Hans (Eds.), Advances in Biomedical Spectroscopy, volume 2:Biological and Biomedical Infrared Spectroscopy, IOS press,2009, p.133.
[36]Gazi E, Dwyer J. Lockyer NP, Miyan J, Gardner P, Hart CA, Brown MD, Clarke NW.2005. A study of cytokinetic and motile prostate cancer cells using synchrotron-based FTIR microspecrtoscopic imaging [J]. Vibrational Spectroscopy 38:193-201.
[37]Dumas P, Sockalingum GD, Sule-suso J.2007. Adding synchrotron radiation to infrared microspectroscopy:what's new in biomedical applications? [J]. Trends. BiotechnoL,25:40-44.
[38]Liu MJ, Wang Z, Wu RC,Sun SQ, Wu QY_ 2003. Monitoring all-transretinoic acid-induced differentiation of human acute promyelocytic leukemia NB4 cells by Fourier-transform infrared spectroscopy [J]. Leukemia,17:1670-1674.
[39]Wang X, Qi ZM, Liu XC, Wang SY, Li CX, Liu G, Xiong Y, Li TT, Tao JQ, Tian YC. 2010.The comparison of hair from gastric cancer patients and from healthy persons studied by infrared microspectroscopy and imaging using synchrotron radiation [J], Cancer. Epidemiol.,34: 453-456.
[40]Cai SW, Singh BR.1999. Identification of P-turn and random coil amide III infrared bands for secondary structure estimation of proteins [J]. Biophys. Chem.80:7-20.
[41]Chen YJ, Cheng YD, Liu HY, Lin PY, Wang CS.2006. Observation of biochemical imaging changes in human pancreatic cancer tissue using Fourier-transform infrared microspectroscopy [J]. Chang Gung. Med. J.,29:518-27.