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Ann Thorac Surg 2005;80:1028-1032
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Expression of Bone Morphogenetic Proteins in Human Lung Carcinomas

Elaine M. Langenfeld, BS a , John Bojnowski, BS b , John Perone, MD a , John Langenfeld, MD b , *

a Department of Surgery, Division of Surgical Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey
b Department of Surgery, Division of Thoracic Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Accepted for publication March 23, 2005.

* Address reprint requests to Dr Langenfeld, Division of Thoracic Surgery, UMDNJ-Robert Wood Johnson Medical School, MEB 534, One Robert Wood Johnson Place, PO Box 19, New Brunswick, NJ08903-0019. (Email: langenje{at}umdnj.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The bone morphogenetic proteins (BMP) are phytogenetically conserved proteins, which are essential for embryonic development. Bone morphogenetic protein-2 (BMP-2) was recently shown to be expressed in a small sample of lung carcinomas. Studies have suggested that BMP-2 may enhance tumor growth. The present study examined which BMP family members are expressed in non-small cell lung carcinomas (NSCLC). Furthermore, the frequency of BMP-2 overexpression and the types of lung carcinomas expressing BMP-2 were determined.

METHODS: Tissue samples were obtained from the operating room and frozen in liquid nitrogen. Samples included metastatic NSCLC, benign lung tumors, adenocarcinoma, squamous cell carcinoma, bronchioloalveolar, and neuroendocrine carcinomas. Paired normal lung tissues served as the controls. The BMP-2, BMP-4, BMP-6, BMP-7, and growth differentiation factor 5 (GDF-5) expressions were examined by Western blot analysis.

RESULTS: The BMP-4, BMP-6, BMP-7, and GDF-5 were infrequently expressed in NSCLC. The BMP-2 was expressed in 41 of 42 NSCLC with minimal expression in normal lung tissue; BMP-2 was expressed 17 fold higher than that of normal lung tissue. The BMP-2 was over-expressed in all subtypes of NSCLC, including neuroendocrine carcinomas. The BMP-2 expression was similar between squamous cell carcinomas and adenocarcinomas; however, bronchioloalveolar carcinomas tended to have a lower level of expression. The BMP-2 was not significantly expressed in benign lung tumors.

CONCLUSIONS: Bone morphogenetic protein-2 is the predominant family member expressed in NSCLC. The BMP-2 is overexpressed in the majority of human lung carcinomas independent of cell type.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
This study demonstrates the frequent expression of a protein which is normally active during embryonic development.

Using representational difference analysis, we identified that bone morphogenetic protein-2 (BMP-2) is expressed in non-small cell lung cancer (NSCLC) [1]. The BMP-2 was originally described because it induces the entire cascade of endochondral bone formation when introduced at an ectopic site [2]. The BMP-2 is now known to be a multipurpose cytokine. The BMP-2 and the highly homologous BMP-4 are essential for normal embryonic development from insects to humans [3]. During development BMP-2/4 are required for the formation of many organs, including the lung [4]. The BMP-2/4 function as morphogens inducing self-renewal of mouse embryonic stem cells [5] and inducing differentiation of several types of stem progenitors [6]. Since recent studies have shown that aberrant expression of embryonic proteins have an important role in the development of cancer [7–10], we have further investigated the significance of BMP-2 in lung carcinomas.

The BMPs are members of the transforming growth factor (TGF) superfamily. The BMPs are produced as precursor proteins, which are cleaved forming a 14 kD mature active protein [11]. The mature BMP binds serine kinase receptors (BMP IA/BMP IB) leading to the recruitment of the BMP II receptor, which then phosphorylates and activates the Smad 1, 5, or 8 transcription factor [12]. The Smad 1, 5, or 8 then activates the transcription of downstream genes. Although BMPs are thought to regulate signaling predominately through Smad 1/5 they have also been shown to induce signaling through Smad 1/5 independent pathways [13].

Studies examining the biological significance of BMP-2 in cancer have only recently been reported. The BMP-2 was shown to increase the invasiveness of melanoma and lung cancer cell lines [14]. The A549 cells coinjected with Affi-Blue agarose beads coated with BMP-2 into nude mice had a 50% increase in tumor growth, as compared to controls [14]. The A549 cells coinjected with the BMP-2 antagonist noggin [15] had a significant decrease in tumor growth [14]. Studies reporting the affects of BMPs on proliferation of tumor cells in vitro have been conflicting. The addition of recombinant BMP-2 or BMP-4 to cancer cell lines cultured in serum free medium led to growth inhibition [16, 17]. However, transfection of a dominant negative BMP II receptor complementary (c)DNA into breast cancer cell lines inhibited proliferation, suggesting that the BMPs stimulate proliferation [18].

Studies have also suggested that the BMPs may have a role in angiogenesis. Functional knockout of the BMP transcription factor Smad 5 in mice leads to defects in vasculogenesis [19]. Knockout of Id 1–3, which are direct targets of BMP-2, also results in defects in vasculogenesis [20]. The BMP-2 stimulates the proliferation and tube formation of endothelial cells [1], which occurs in part through the activation of Id-1 and Erk 1/2 [1, 21]. Recombinant BMP-2 significantly increased blood vessel formation in tumors formed by A549 cells in nude mice [1]. Decreasing BMP-2 expression in A549 cells by anti-sense transfection caused a significant decrease in blood vessel formation [1]. Further supporting a role for BMP-2 in lung cancer is a study using microarray analysis of stage I NSCLC demonstrating that high BMP-2 expression was associated with a worse prognosis [22].

The frequency and types of lung carcinomas expressing BMP-2 are not known. It is also not known whether other BMP family members are expressed in lung carcinomas. The purpose of this study was to characterize the expression of BMP-2 and other family members in lung carcinomas.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Reagents
Primary antibodies mouse anti-BMP-2 (clone 65529), mouse anti-BMP-4 (clone 66119), mouse anti-BMP-6 (74219), mouse anti-BMP-7, and goat anti-growth differentiation factor 5 (anti-GDF-5) were purchased from R & D Systems (Minneapolis, MN). Recombinant proteins BMP-2, BMP-4, BMP-6, and GDF-5 were purchased from R & D Systems and were used as positive controls on Western blot analysis.

Tissue Specimens
Tissues were obtained directly from the operating room and immediately frozen in liquid nitrogen. All samples had ischemic times less than 20 minutes. Only samples without significant necrosis were used.

Western Blot Analysis
Total cellular protein was obtained using RIPA buffer [14]. Total cellular protein was analyzed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to nitrocellulose (Schleicher and Schuell, Keene, NH) at 35 V for 16 hours at 4°C. The blots were then incubated overnight at 4°C with the appropriate primary antibody. Specific proteins were detected using the enhanced chemiluminescence system (Amersham, Arlington Heights, IL).

Pixel Density
To compare differences in the level of BMP expression the mature BMP protein detected on the developed film was scanned into Adobe Photo Shop. The intensity of each band was then determined using National Institutes of Health (NIH) imaging software.

Statistical Analysis
To evaluate multiple groups a one-way analysis of variance followed by Fisher’s least significant difference post hoc test was used to compare individual means. To compare two groups a Student’s t test was used. Differences with p values of 0.05 or less were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Expression of BMP Family Members in NSCLC
We found, by Western Blot analysis, high expression of the mature BMP-2 protein in the majority of NSCLC with little or no detectable expression in normal lung tissue (Fig 1). The BMP-2 was found to be expressed in all but one of the NSCLC examined (Table 1). The mature BMP-6 protein was detected in all the NSCLC examined, however it was expressed only slightly higher than that of normal lung tissue (Fig 1 and Table 1). Only low levels of expression of BMP-4 and GDF-5 were seen in a small percentage of NSCLC (Table 1). The BMP-7 was not detected in any of the 17 NSCLC examined (Table 1). These data demonstrate that BMP-2 is the predominant family member expressed in NSCLC.



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  		Fig 1. Representative immunoblot demonstrating the expression of the mature active protein of BMP-2 and BMP-6 in NSCLC and normal lung (BMP = bone morphogenetic protein; N = normal lung; NSCLC = non-small cell lung carcinoma; T = tumor tissue). The expression of actin was also determined to verify equivalent loading. The recombinant BMP protein was used as a positive control.

 

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  		Table 1. BMP Expression in NSCLC Versus Normal Lung
 
BMP-2 Expression in NSCLC
To assess the level of BMP expression in tumors in comparison with normal lung tissue, Western blots were scanned and pixel density of the mature BMP protein determined by NIH imaging software. The BMP-6 expression in NSCLC was only slightly higher than that of normal lung tissue and was not statistically significant (Table 1). BMP-2 expression in NSCLC was 17-fold higher in comparison to normal lung tissue. BMP-2 was expressed at least threefold higher than normal lung in all 31 adenocarcinomas and squamous cell carcinomas examined. The only tumor not expressing BMP-2 was a bronchioloalveolar carcinoma. We next compared the level of BMP-2 expression in the different types of lung carcinomas. There was no difference in BMP-2 expression between adenocarcinomas and squamous cell carcinomas (Table 2). Although 3 of 4 bronchioloalveolar carcinomas expressed BMP-2 higher than that of normal lung, the level of expression was less than that of adenocarcinomas and squamous cell carcinomas (Table 2). To determine whether BMP-2 expression is maintained in metastatic disease, we examined the level of BMP-2 expressed in NSCLC that had metastasized to mediastinal lymph nodes. In metastatic NSCLC, BMP-2 expression was similar to that of adenocarcinomas and squamous cell carcinomas (Table 2).


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  		Table 2. BMP-2 Expression in Lung Tumors
 
BMP-2 Expression in Neuroendocrine Tumors
The level of BMP-2 expression in neuroendocrine tumors originating from the lung was similar to adenocarcinomas and squamous cell carcinomas. All of the eight neuroendocrine tumors examined over-expressed BMP-2 (Table 2). We examined four typical carcinoid tumors, one atypical carcinoid, two large cell neuroendocrine carcinomas, and one small cell carcinoma. In this small collection of neuroendocrine tumors, BMP-2 expression appeared similar among the different cell types. To assess whether high levels of BMP-2 occur only in malignant tumors, we examined its expression in benign lung tumors. In the 3 hamartomas and the one benign fibrous tumor, BMP-2 was either not detected or expressed at the same level as normal lung tissue (Table 2). Furthermore, lung biopsies obtained from patients with interstitial lung diseases did not reveal any significant BMP-2 expression (Table 2). These data suggest that aberrant BMP-2 expression is associated only with malignant tumors and is not an acute phase protein.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This paper demonstrates a high and frequent overexpression of BMP-2 in lung carcinomas. The mature active form of BMP-2 was aberrantly expressed in 98% of the NSCLC examined. BMP-2 is expressed in all types of lung carcinomas including both epithelial and neuroendocrine derived tumors. All of the adenocarcinomas and squamous cell carcinomas were found to overexpress BMP-2. The same level of BMP-2 expression was seen in both adenocarcinomas and squamous cell carcinomas. In this small analysis of bronchioloalveolar carcinomas, BMP-2 expression was less than that of other types of lung carcinomas. The only NSCLC not overexpressing BMP-2 was a bronchioloalveolar carcinoma. Although bronchioloalveolar carcinomas are classified as adenocarcinomas they are not invasive tumors, which may explain the lower level of expression. The lack of significant BMP-2 expression in benign lung tumors suggests that BMP-2 is active only in malignant tumors. Furthermore, this study suggests that other BMP family members do not have significant activity in NSCLC.

The aberrant expression of embryonic proteins in cancer has highlighted the importance of this class of genes in the development of cancer. Sonic hedgehog [7], Wnt [8], notched [9], and vascular endothelial growth factor [10] are essential for embryonic development and have been shown to have an important role in the growth of several carcinomas, including lung. This is of particular interest since the activities of these embryonic proteins have been shown to be associated with that of BMP-2/4 during development [23–26]. Recent studies have suggested that tumor growth and metastasis originates from a small subset of cancer cells, which can self-renew to form daughter cells [27, 28]. These studies suggest that tumor growth is dependent on "stem cell-like" tumor cells. It will be of interest to see if BMP-2 and other embryonic proteins regulate stem cell-like cancer cells.

We found BMP-2 to significantly enhance tumor growth of A549 cells in nude mice [14]. However, reports on the autocrine affects of BMP-2 on the proliferation of cancer cell lines in vitro have been conflicting [16–18]. The in vivo and in vitro affects of BMP-2 on proliferation may be quite different. During development, BMP-2/4 forms a tightly regulated functional gradient, which allows it to elicit a variety of biological responses [29, 30]. The activity of BMP-2/4 is dependent on concentration and the presence of intracellular and extracellular antagonists [15, 31]. The culture conditions also make a significant difference on how cells respond to BMP-2. We found that BMP-2 stimulates proliferation of A549 cells cultured in medium containing serum, while in serum free medium it causes growth inhibition (unpublished data). BMP-2 stimulated cell growth of prostate cancer cells in androgen free culture conditions [32]. However, in the presence of androgen BMP-2 inhibited cell growth [32].

Our studies suggest that BMP-2 promotes tumor growth through both autocrine and paracrine mechanisms. BMP-2 caused a significant increase in blood vessel formation in developing tumors [1]. Anti-sense transfection of BMP-2 cDNA into A549 cells leads to a decrease in angiogenesis. BMP-2 and BMP-6 have been shown to directly stimulate endothelial cells in vitro [1, 21]. These data suggest that BMP-2 is secreted from tumor cells, which then stimulate angiogenesis by activating endothelial cells. However, BMP-2 may also stimulate angiogenesis by other mechanisms. BMP-2 is thought to stimulate angiogenesis during bone formation by stimulating vascular endothelial growth factor [33].

The frequent expression of BMP-2 in lung cancer suggests it may have more of a role in the formation of cancer rather that progression. However, the level of BMP-2 messenger ribonucleic acid (mRNA) did correlate with prognosis in stage I NSCLC [22] and in osteosarcomas [34]. Our study did not assess whether protein expression of BMP-2 corresponded to survival. Chemiluminescence used in our Western blot analysis may not be the best method to detect a small difference in expression levels, since its signal is not directly linear with the amount of protein. Our future studies will address how BMP-2 affects the progression and metastasis of lung carcinomas.

We believe that BMP-2 may be a good target for therapy in lung cancer for several reasons. BMP-2 is expressed in the majority of lung carcinomas. The frequency of other oncogenes expressed in lung cancer is lower than that for BMP-2. Epidermal growth factor is overexpressed in approximately 32% of NSCLC [35]. Mutation activating Ras occur in only 25% of lung adenocarcinomas and are not found in other types of lung carcinomas [36]. The myc amplification occurs in approximately 20% of NSCLC. Inactivation of tumor-suppressors p16 [37] and p53 [38] occurs in approximately 50% of NSCLC; however, they may represent more difficult targets since the genes are already inactivated. BMP-2 expression in lung tumors is high and there is little to no expression in normal lung tissue, implying that anti-BMP-2 therapy would have minimal toxicity. Studies suggest that BMP-2 may have significant biological activity in lung cancer by stimulating invasion and tumor growth. However, further studies are needed to determine whether inhibition of BMP-2 signaling will significantly alter tumor growth, invasion, and/or metastasis.

In summary, BMP-2 is overexpressed in all types of lung carcinomas. If biological significance of BMP-2 is substantiated, it would make BMP-2 an attractive target in cancer therapy because of the high level of expression in tumors in comparison with normal lung tissue.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was funded by NIH Grant No. CA91919-01A1 and The Thoracic Surgery Foundation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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