臺灣博碩士論文加值系統

癌症病人的死亡，主要是因為腫瘤細胞侵犯鄰近組織及轉移到其他部位所造成。肺癌是台灣目前最多的癌症死因。肺腺癌是非小細胞肺癌中的主要分類，由於發生在周邊位置的緣故，肺腺癌非常難以早期偵測。因此，我們對於了解原發性肺腺癌如何轉變為侵犯性肺腺癌非常感興趣。
在本研究我們從原位和侵犯肺腺癌組織中應用顯微雷射捕捉技術和cDNA晶片表現技術來萃取RNA和分析與侵犯相關的差異表現基因。大約有45個與侵犯相關的基因具有3倍以上的表現量差異，包括matrix metalloproteinases, keratin 6A, prion 和未知的基因。
在使用分子病理學和免疫組織染色方法確定表現差異後，我們找到了普恩蛋白(prion)。異常的Prion是造成狂牛病（BSE）及庫賈氏症（Creutzfeldt-Jakob disease，CJD）等神經退化性疾病的病因。然而，吾人對於存在於一般組織中的正常prion的功能還不清楚。我們利用免疫染色法在肺腺癌病人中研究prion的表現，發現12個原發性肺腺癌沒有表現prion，而在92個侵犯性肺腺癌有91個有高度表現prion。另一方面，我們在具有不同侵犯能力的肺腺癌細胞株中進行半定量RT-PCR來研究prion的表現量，發現侵犯能力低的細胞株其表現量低，而侵犯能力高的細胞株其prion表現量高。我們的結果推測在肺腺癌中prion與腫瘤侵犯具有相關性。

The morbidity and mortality of cancer patients mainly result from the invasion of tumor cells into neighboring tissues and tumor metastases to remote sites. Lung cancer currently leads the cancer death rate in Taiwan. Adenocarcinoma is the major subtype of pulmonary non-small cell carcinomas and tends to occur at the peripheral pulmonary parenchyma, which renders early diagnoses extremely difficult. It would be interesting to understand how the in situ lung adenocarcinoma transforms into invasive lung adenocarcinoma. In this study, we performed laser capture microdissection and cDNA microarray analysis on RNA extracted from in situ and invasive pulmonary adenocarcinoma tissues to analyze the genetic profiles and differentially expressed genes associated with invasion. Approximately 45 genes with 3-fold up-regulation associated with tumor invasion were obtained, including matrix metalloproteinases, keratin 6A, prion and unknown genes.
After confirming the differential expression patterns using molecular pathology and immunohistochemical methods, we focused on the study of cellular prion protein (PrPc). Accumulation of abnormal prion protein (PrPSc) causes neurodegenerative diseases such as Bovine Spongiform Encephalopathy (BSE) and Creutzfeld-Jakob Disease (CJD). The cellular prion protein is a ubiquitous host protein expressed by all known mammals, but its normal function was not clear. We studied the expression of prion in pulmonary adenocarcinoma patients by immunohistochemistry and found that while 12 in situ adenocarcinomas do not express prion, 91 out of 92 invasive adenocarcinomas have high expression level of prion. On the other hands, we performed semi-quantitative RT-PCR to investigate the expression levels of prion in lung adenocarcinoma cell lines with variable invasiveness ability and found that there is low expression in the low-invasiveness cell lines and high expression in the high-invasiveness cell lines. Our data suggest that prion is associated with tumor invasion in pulmonary adenocarcinomas.

1.Arra-Mehrpour,M, Arrabal,S, Jalil,A, Pinson,X, Gaudin,C, Pietu,G, Pitaval,A, Ripoche,H, Eloit,M, Dormont,D, and Chouaib,S (2004) Prion protein prevents human breast carcinoma cell line from tumor necrosis factor alpha-induced cell death. Cancer Res, 64, 719-727.
2.Bashyam,MD (2002) Understanding cancer metastasis: an urgent need for using differential gene expression analysis. Cancer, 94, 1821-1829.
3.Beer,DG, Kardia,SL, Huang,CC, Giordano,TJ, Levin,AM, Misek,DE, Lin,L, Chen,G, Gharib,TG, Thomas,DG, Lizyness,ML, Kuick,R, Hayasaka,S, Taylor,JM, Iannettoni,MD, Orringer,MB, and Hanash,S (2002) Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med, 8, 816-824.
4.Bhattacharjee,A, Richards,WG, Staunton,J, Li,C, Monti,S, Vasa,P, Ladd,C, Beheshti,J, Bueno,R, Gillette,M, Loda,M, Weber,G, Mark,EJ, Lander,ES, Wong,W, Johnson,BE, Golub,TR, Sugarbaker,DJ, and Meyerson,M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A, 98, 13790-13795.
5.Bodey,B, Bodey,B, Jr., Siegel,SE, and Kaiser,HE (2000) Immunocytochemical detection of MMP-3 and -10 expression in hepatocellular carcinomas. Anticancer Res, 20, 4585-4590.
6.Brown,DR, Nicholas,RS, and Canevari,L (2002) Lack of prion protein expression results in a neuronal phenotype sensitive to stress. J Neurosci Res, 67, 211-224.
7.Chen,JJ, Peck,K, Hong,TM, Yang,SC, Sher,YP, Shih,JY, Wu,R, Cheng,JL, Roffler,SR, Wu,CW, and Yang,PC (2001) Global analysis of gene expression in invasion by a lung cancer model. Cancer Res, 61, 5223-5230.
8.Chiarini,LB, Freitas,AR, Zanata,SM, Brentani,RR, Martins,VR, and Linden,R (2002) Cellular prion protein transduces neuroprotective signals. EMBO J, 21, 3317-3326.
9.Chomczynski P and Sacchi N. (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 162, 156-159.
10.Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R, and Wu CW. (1997) Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 17, 353-360.
11.Clarke,PA, te,PR, Wooster,R, and Workman,P (2001) Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential. Biochem Pharmacol, 62, 1311-1336.
12.Comoglio,PM and Trusolino,L (2002) Invasive growth: from development to metastasis. J Clin Invest, 109, 857-862.
13.Curran,S, McKay,JA, McLeod,HL, and Murray,GI (2000) Laser capture microscopy. Mol Pathol, 53, 64-68.
14.Curran,S and Murray,GI (1999) Matrix metalloproteinases in tumour invasion and metastasis. J Pathol, 189, 300-308.
15.Davidson,B, Konstantinovsky,S, Nielsen,S, Dong,HP, Berner,A, Vyberg,M, and Reich,R (2004) Altered expression of metastasis-associated and regulatory molecules in effusions from breast cancer patients: a novel model for tumor progression. Clin Cancer Res, 10, 7335-7346.
16.De,MG, Guglielmi,A, Verlato,G, Tomezzoli,A, Pelosi,G, Schiavon,I, and Cordiano,C (1998) Prognostic significance of 67-kDa laminin receptor expression in advanced gastric cancer. Oncology, 55, 456-460.
17.Department of Health Taiwan. (2002) Health Statistics. Taipei, Taiwan.
18.DeRisi,J, Penland,L, Brown,PO, Bittner,ML, Meltzer,PS, Ray,M, Chen,Y, Su,YA, and Trent,JM (1996) Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet, 14, 457-460.
19.Du,J, Pan,Y, Shi,Y, Guo,C, Jin,X, Sun,L, Liu,N, Qiao,T, and Fan,D (2005) Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR. Int J Cancer, 113, 213-220.
20.Emmert-Buck,MR, Bonner,RF, Smith,PD, Chuaqui,RF, Zhuang,Z, Goldstein,SR, Weiss,RA, and Liotta,LA (1996) Laser capture microdissection. Science, 274, 998-1001.
21.Engbring,JA and Kleinman,HK (2003) The basement membrane matrix in malignancy. J Pathol, 200, 465-470.
22.Fend,F and Raffeld,M (2000) Laser capture microdissection in pathology. J Clin Pathol, 53, 666-672.
23.Garber,ME, Troyanskaya,OG, Schluens,K, Petersen,S, Thaesler,Z, Pacyna-Gengelbach,M, van de,RM, Rosen,GD, Perou,CM, Whyte,RI, Altman,RB, Brown,PO, Botstein,D, and Petersen,I (2001) Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A, 98, 13784-13789.
24.Gauczynski,S, Peyrin,JM, Haik,S, Leucht,C, Hundt,C, Rieger,R, Krasemann,S, Deslys,JP, Dormont,D, Lasmezas,CI, and Weiss,S (2001) The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J, 20, 5863-5875.
25.Goto,K, Yokose,T, Kodama,T, Nagai,K, Nishiwaki,Y, Ando,M, Mukai,K, and Ochiai,A (2001) Detection of early invasion on the basis of basement membrane destruction in small adenocarcinomas of the lung and its clinical implications. Mod Pathol, 14, 1237-1245.
26.Graner,E, Mercadante,AF, Zanata,SM, Forlenza,OV, Cabral,AL, Veiga,SS, Juliano,MA, Roesler,R, Walz,R, Minetti,A, Izquierdo,I, Martins,VR, and Brentani,RR (2000a) Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res Mol Brain Res, 76, 85-92.
27.Graner,E, Mercadante,AF, Zanata,SM, Martins,VR, Jay,DG, and Brentani,RR (2000b) Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett, 482, 257-260.
28.Greenlee,RT, Murray,T, Bolden,S, and Wingo,PA (2000) Cancer statistics, 2000. CA Cancer J Clin, 50, 7-33.
29.Hanahan,D and Weinberg,RA (2000) The hallmarks of cancer. Cell, 100, 57-70.
30.Harris,DA (1999) Cellular biology of prion diseases. Clin Microbiol Rev, 12, 429-444.
31.Harris,DA, Falls,DL, Johnson,FA, and Fischbach,GD (1991) A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity. Proc Natl Acad Sci U S A, 88, 7664-7668.
32.Hasegawa,S, Furukawa,Y, Li,M, Satoh,S, Kato,T, Watanabe,T, Katagiri,T, Tsunoda,T, Yamaoka,Y, and Nakamura,Y (2002) Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes. Cancer Res, 62, 7012-7017.
33.Herms,JW, Madlung,A, Brown,DR, and Kretzschmar,HA (1997) Increase of intracellular free Ca2+ in microglia activated by prion protein fragment. Glia, 21, 253-257.
34.Ho CC, Huang PH, Huang HY, Chen YH, Yang PC, and Hsu SM. (2002) Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol. 161, 1647-1656.
35.Hoang,CD, D'Cunha,J, Tawfic,SH, Gruessner,AC, Kratzke,RA, and Maddaus,MA (2004) Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden. J Thorac Cardiovasc Surg, 127, 1332-1341.
36.Huang,Z, Prusiner,SB, and Cohen,FE (1996) Structures of prion proteins and conformational models for prion diseases. Curr Top Microbiol Immunol, 207, 49-67.
37.Ji,P, Diederichs,S, Wang,W, Boing,S, Metzger,R, Schneider,PM, Tidow,N, Brandt,B, Buerger,H, Bulk,E, Thomas,M, Berdel,WE, Serve,H, and Muller-Tidow,C (2003) MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene, 22, 8031-8041.
38.Joseph Sambrook and David W.Russell (2001). Molecular Cloning, 3rd ed. Cold Spring Harbor New York; Cold Spring Harbor Laboratory Press.
39.Kerkela,E, la-aho,R, Klemi,P, Grenman,S, Shapiro,SD, Kahari,VM, and Saarialho-Kere,U (2002) Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome. J Pathol, 198, 258-269.
40.Kerkela,E, la-aho,R, Lohi,J, Grenman,R, Kahari,V, and Saarialho-Kere,U (2001) Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer, 84, 659-669.
41.Kitahara,O, Furukawa,Y, Tanaka,T, Kihara,C, Ono,K, Yanagawa,R, Nita,ME, Takagi,T, Nakamura,Y, and Tsunoda,T (2001) Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res, 61, 3544-3549.
42.Kitamura,H, Oosawa,Y, Kawano,N, Kameda,Y, Hayashi,H, Nakatani,Y, Udaka,N, Ito,T, and Miyazaki,K (1999) Basement membrane patterns, gelatinase A and tissue inhibitor of metalloproteinase-2 expressions, and stromal fibrosis during the development of peripheral lung adenocarcinoma. Hum Pathol, 30, 331-338.
43.Kobayashi,K, Nishioka,M, Kohno,T, Nakamoto,M, Maeshima,A, Aoyagi,K, Sasaki,H, Takenoshita,S, Sugimura,H, and Yokota,J (2004) Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo. Oncogene, 23, 3089-3096.
44.Koo,TH, Lee,JJ, Kim,EM, Kim,KW, Kim,HD, and Lee,JH (2002) Syntenin is overexpressed and promotes cell migration in metastatic human breast and gastric cancer cell lines. Oncogene, 21, 4080-4088.
45.Kumaki,F, Matsui,K, Kawai,T, Ozeki,Y, Yu,ZX, Ferrans,VJ, and Travis,WD (2001) Expression of matrix metalloproteinases in invasive pulmonary adenocarcinoma with bronchioloalveolar component and atypical adenomatous hyperplasia. Am J Pathol, 159, 2125-2135.
46.Kuman V, Abbas AK, and Fausto N. (2004). Robbins and Cotran Pathologic Basis of Ddisease, 7th ed. W.B. Saunders Co. Philadelphia.
47.Lee,KS, Linden,R, Prado,MA, Brentani,RR, and Martins,VR (2003) Towards cellular receptors for prions. Rev Med Virol, 13, 399-408.
48.Lehmann,S and Harris,DA (1995) A mutant prion protein displays an aberrant membrane association when expressed in cultured cells. J Biol Chem, 270, 24589-24597.
49.Lin,TS, Chiou,SH, Wang,LS, Huang,HH, Chiang,SF, Shih,AY, Chen,YL, Chen,CY, Hsu,CP, Hsu,NY, Chou,MC, Kuo,SJ, and Chow,KC (2004) Expression spectra of matrix metalloproteinases in metastatic non-small cell lung cancer. Oncol Rep, 12, 717-723.
50.Liu,SC, Bassi,DE, Zhang,SY, Holoran,D, Conti,CJ, and Klein-Szanto,AJ (2002) Overexpression of cyclin D2 is associated with increased in vivo invasiveness of human squamous carcinoma cells. Mol Carcinog, 34, 131-139.
51.Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, and Darnell JE (1999). Molecular Cell Biology, 4th ed. New York: W. H. Freeman and Company..
52.Luca,M, Huang,S, Gershenwald,JE, Singh,RK, Reich,R, and Bar-Eli,M (1997) Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol, 151, 1105-1113.
53.Ma,XJ, Salunga,R, Tuggle,JT, Gaudet,J, Enright,E, McQuary,P, Payette,T, Pistone,M, Stecker,K, Zhang,BM, Zhou,YX, Varnholt,H, Smith,B, Gadd,M, Chatfield,E, Kessler,J, Baer,TM, Erlander,MG, and Sgroi,DC (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci U S A, 100, 5974-5979.
54.Mandel,M and Higa,A (1970) Calcium-dependent bacteriophage DNA infection. J Mol Biol, 53, 159-162.
55.Mareel,M and Leroy,A (2003) Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev, 83, 337-376.
56.Massimino,ML, Griffoni,C, Spisni,E, Toni,M, and Tomasi,V (2002) Involvement of caveolae and caveolae-like domains in signalling, cell survival and angiogenesis. Cell Signal, 14, 93-98.
57.Mathew,R, Khanna,R, Kumar,R, Mathur,M, Shukla,NK, and Ralhan,R (2002) Stromelysin-2 overexpression in human esophageal squamous cell carcinoma: potential clinical implications. Cancer Detect Prev, 26, 222-228.
58.Miura,K, Bowman,ED, Simon,R, Peng,AC, Robles,AI, Jones,RT, Katagiri,T, He,P, Mizukami,H, Charboneau,L, Kikuchi,T, Liotta,LA, Nakamura,Y, and Harris,CC (2002) Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res, 62, 3244-3250.
59.Montuenga,LM and Mulshine,JL (2000) New molecular strategies for early lung cancer detection. Cancer Invest, 18, 555-563.
60.Mott,JD and Werb,Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol, 16, 558-564.
61.Mouillet-Richard,S, Ermonval,M, Chebassier,C, Laplanche,JL, Lehmann,S, Launay,JM, and Kellermann,O (2000) Signal transduction through prion protein. Science, 289, 1925-1928.
62.Mountain,CF (1995) New prognostic factors in lung cancer. Biologic prophets of cancer cell aggression. Chest, 108, 246-254.
63.Mountain,CF (1986) A new international staging system for lung cancer. Chest, 89, 225S-233S.
64.Mulshine,JL and Henschke,CI (2000) Prospects for lung-cancer screening. Lancet, 355, 592-593.
65.Nakamura,H, Fujii,Y, Ohuchi,E, Yamamoto,E, and Okada,Y (1998) Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem, 253, 67-75.
66.Nakano,KY, Iyama,KI, Mori,T, Yoshioka,M, Hiraoka,T, Sado,Y, and Ninomiya,Y (2001) Loss of alveolar basement membrane type IV collagen alpha3, alpha4, and alpha5 chains in bronchioloalveolar carcinoma of the lung. J Pathol, 194, 420-427.
67.Nishidate,T, Katagiri,T, Lin,ML, Mano,Y, Miki,Y, Kasumi,F, Yoshimoto,M, Tsunoda,T, Hirata,K, and Nakamura,Y (2004) Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection: identification of genes associated with progression and metastasis. Int J Oncol, 25, 797-819.
68.O'Driscoll,L, Linehan,R, Liang,YH, Joyce,H, Oglesby,I, and Clynes,M (2002) Galectin-3 expression alters adhesion, motility and invasion in a lung cell line (DLKP), in vitro. Anticancer Res, 22, 3117-3125.
69.Okabe,H, Satoh,S, Kato,T, Kitahara,O, Yanagawa,R, Yamaoka,Y, Tsunoda,T, Furukawa,Y, and Nakamura,Y (2001) Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res, 61, 2129-2137.
70.Perng DW, Perng RP, Kuo BI, and Chiang SC. (1996) The variation of cell type distribution in lung cancer: a study of 10,910 cases at a medical center in Taiwan between 1970 and 1993. Jpn.J Clin.Oncol. 26, 229-233.
71.Petitclerc,E, Boutaud,A, Prestayko,A, Xu,J, Sado,Y, Ninomiya,Y, Sarras,MP, Jr., Hudson,BG, and Brooks,PC (2000) New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J Biol Chem, 275, 8051-8061.
72.Rieger,R, Edenhofer,F, Lasmezas,CI, and Weiss,S (1997) The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med, 3, 1383-1388.
73.Sarantopoulos,GP, Gui,D, Shintaku,P, Hong,L, Wang,YY, Yap,CS, and Fishbein,MC (2004) Immunohistochemical analysis of lung carcinomas with pure or partial bronchioloalveolar differentiation. Arch Pathol Lab Med, 128, 406-414.
74.Satoh,J, Kuroda,Y, and Katamine,S (2000) Gene expression profile in prion protein-deficient fibroblasts in culture. Am J Pathol, 157, 59-68.
75.Schena,M, Shalon,D, Davis,RW, and Brown,PO (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science, 270, 467-470.
76.Silva,CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene, 23, 8017-8023.
77.Songur,N, Kuru,B, Kalkan,F, Ozdilekcan,C, Cakmak,H, and Hizel,N (2004) Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer. Tumori, 90, 196-200.
78.Sund,M, Xie,L, and Kalluri,R (2004) The contribution of vascular basement membranes and extracellular matrix to the mechanics of tumor angiogenesis. APMIS, 112, 450-462.
79.Takenaka,Y, Fukumori,T, and Raz,A (2004) Galectin-3 and metastasis. Glycoconj J, 19, 543-549.
80.Thiery,JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2, 442-454.
81.Thorns,V, Walter,GF, and Thorns,C (2003) Expression of MMP-2, MMP-7, MMP-9, MMP-10 and MMP-11 in human astrocytic and oligodendroglial gliomas. Anticancer Res, 23, 3937-3944.
82.To,Y, Dohi,M, Matsumoto,K, Tanaka,R, Sato,A, Nakagome,K, Nakamura,T, and Yamamoto,K (2002) A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line. Am J Respir Cell Mol Biol, 27, 220-226.
83.Travis WD, Sobin LH, Colby TV, Corrin B, and et al (1999). Histologic typing of Lung and Pleural Tumors. WHO International Histological Classification of Tumours, 3rd ed. Berlin, Springer-Verlag.
84.Vaarala,MH, Porvari,K, Kyllonen,A, and Vihko,P (2000) Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression. Lab Invest, 80, 1259-1268.
85.Van,TC, Alain,T, Kossakowska,AE, Urbanski,S, Potworowski,EF, and St-Pierre,Y (2004b) Stromelysin-2 (matrix metalloproteinase 10) is inducible in lymphoma cells and accelerates the growth of lymphoid tumors in vivo. J Immunol, 173, 3605-3611.
86.Weissmann,C (2004) The state of the prion. Nat Rev Microbiol, 2, 861-871.
87.Weitberg AB (2001). Cancer of the lung :from molecular biology to treatment guidelines. Totowa, N.J. Humana Press.
88.Xu,J, Rodriguez,D, Petitclerc,E, Kim,JJ, Hangai,M, Moon,YS, Davis,GE, and Brooks,PC (2001) Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol, 154, 1069-1079.