The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells

被引:156
作者
Langenfeld, EM
Calvano, SE
Abou-Nukta, F
Lowry, SF
Amenta, P
Langenfeld, J
机构
[1] UMDNJ, Robert Wood Johnson Med Sch, Dept Surg, Div Thorac Surg, New Brunswick, NJ 08903 USA
[2] UMDNJ, Robert Wood Johnson Med Sch, Dept Surg, Div Surg Sci, New Brunswick, NJ 08903 USA
[3] UMDNJ, Robert Wood Johnson Med Sch, Dept Pathol, New Brunswick, NJ 08903 USA
关键词
D O I
10.1093/carcin/bgg100
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
To help identify genes, which may regulate metastasis in lung cancer, we performed representational difference analysis between a patient-derived non-small cell lung carcinoma (NSCLC) and immortalized normal human bronchial epithelial cells. This analysis revealed that bone morphogenetic proteins-2/4 (BMP) mRNA was expressed in the lung carcinoma. BMP-2/4 are known to induce pluripotent cell differentiation, enhance cell migration and stimulate proliferation during embryonic development. Despite being powerful morphogens it is not known whether BMP-2/4 have significant biological activity in human carcinomas. Furthermore, it has not been established whether the mature active BMP-2/4 protein is aberrantly expressed in patient-derived tumors. The purpose of this study was to determine whether the expression of the mature BMP-2/4 protein is disregulated in human lung carcinomas and to establish whether it has adverse biological activity. This study reveals that the mature BMP-2 protein, but not BMP-4, is highly over-expressed in human NCSLC with little to no expression in normal lung tissue or benign lung tumors. The expression of BMP-2 localized specifically to the cancer cells. Recombinant BMP-2 stimulated in vitro, the migration and invasiveness of the A549 and H7249 human lung cancer cell lines. In vivo, recombinant BMP-2 enhanced the growth of tumors formed from A549 cells injected subcutaneously into nude mice. Furthermore, inhibition of BMP-2 activity with either recombinant noggin or anti-BMP-2 antibody resulted in a significant reduction in tumor growth. This study shows that expression of the mature BMP-2 protein is disregulated in the majority of NSCLC. BMP-2 enhancement of tumor cell migration and invasion, as well as stimulating tumor growth in vivo, suggests it has important biological activity in lung carcinomas.
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页码:1445 / 1454
页数:10
相关论文
共 51 条
[1]   Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: Antagonism by noggin [J].
Abe, E ;
Yamamoto, M ;
Taguchi, Y ;
Lecka-Czernik, B ;
O'Brien, CA ;
Economides, AN ;
Stahl, N ;
Jilka, RL ;
Manolagas, SC .
JOURNAL OF BONE AND MINERAL RESEARCH, 2000, 15 (04) :663-673
[2]  
ABIGAIL S, 1998, SCIENCE, V282, P1136
[3]   In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector [J].
Alden, TD ;
Pittman, DD ;
Hankins, GR ;
Beres, EJ ;
Engh, JA ;
Das, S ;
Hudson, SB ;
Kerns, KM ;
Kallmes, DF ;
Helm, GA .
HUMAN GENE THERAPY, 1999, 10 (13) :2245-2253
[4]  
An J, 1996, EXP HEMATOL, V24, P768
[5]   Bone induction by Escherichia coli-derived recombinant human bone morphogenetic protein-2 compared with Chinese hamster ovary cell-derived recombinant human bone morphogenetic protein-2 [J].
Bessho, K ;
Konishi, Y ;
Kaihara, S ;
Fujimura, K ;
Okubo, Y ;
Iizuka, T .
BRITISH JOURNAL OF ORAL & MAXILLOFACIAL SURGERY, 2000, 38 (06) :645-649
[6]   Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton [J].
Brunet, LJ ;
McMahon, JA ;
McMahon, AP ;
Harland, RM .
SCIENCE, 1998, 280 (5368) :1455-1457
[7]   Endogenous and ectopic expression of noggin suggests a conserved mechanism for regulation of BMP function during limb and somite patterning [J].
Capdevila, J ;
Johnson, RL .
DEVELOPMENTAL BIOLOGY, 1998, 197 (02) :205-217
[8]   IDENTIFICATION OF TRANSFORMING GROWTH-FACTOR-BETA FAMILY MEMBERS PRESENT IN BONE-INDUCTIVE PROTEIN PURIFIED FROM BOVINE BONE [J].
CELESTE, AJ ;
IANNAZZI, JA ;
TAYLOR, RC ;
HEWICK, RM ;
ROSEN, V ;
WANG, EA ;
WOZNEY, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (24) :9843-9847
[9]   BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development [J].
Cui, YZ ;
Jean, F ;
Thomas, G ;
Christian, JL .
EMBO JOURNAL, 1998, 17 (16) :4735-4743
[10]   OSTEOGENIN AND RECOMBINANT BONE MORPHOGENETIC PROTEIN-2B ARE CHEMOTACTIC FOR HUMAN MONOCYTES AND STIMULATE TRANSFORMING GROWTH FACTOR-BETA-1 MESSENGER-RNA EXPRESSION [J].
CUNNINGHAM, NS ;
PARALKAR, V ;
REDDI, AH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (24) :11740-11744