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Annals of Clinical & Laboratory Science 31:369-375 (2001)
© 2001 Association of Clinical Scientists

Gene Expression Patterns of Paired Bronchioloalveolar Carcinoma and Benign Lung Tissue

Leslie O. Goodwin1, James M. Mason1 and Steven I. Hajdu2
1 Department of Research (Molecular Genetics) and 2 Department of Pathology, North Shore-Long Island Jewish Research Institute, Manhasset, New York

Address correspondence to Steven I. Hajdu, M.D., Department of Pathology, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA; tel 516 562 3250; fax 516 562 4591.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
A variant of adenocarcinoma, bronchioloalveolar carcinoma (BAC), has increased in incidence since 1950 and now represents 2–14% of all lung cancers. There has been concomitant diminution in the proportion of squamous cell carcinoma, the most common form of primary lung cancer. The BAC form of adenocarcinoma occurs disproportionately in women, has an earlier age of onset than conventional pulmonary carcinoma, and is not linked to smoking. The increased incidence of BAC in both smokers and non-smokers suggests that BAC may have an environmental etiology other than smoking. To explore this possibility, we compared the patterns of gene expression in paired samples of tumor and normal lung tissue from 3 patients with a pathologic diagnosis of BAC. Characterization of the gene expression patterns of the paired tissue samples was performed by oligonucleotide microarray analysis of 12,000 known genes and expressed sequence tags (ESTs). We identified 12 genes that were up-regulated >=2-fold in all 3 tumors and 6 genes that were down-regulated in all 3 tumors to <=0.20 times the baseline. These findings suggest that large scale transcriptional profiling of BAC tumors may disclose a pattern of altered cellular expression in response to genetic changes, diseases, and environmental insult; such transcriptional profiling may aid in diagnosis and therapy.

(received 29 June 2001; accepted 23 August 2001)

Keywords: lung cancer, bronchioloalveolar carcinoma, oligonucleotide microarray, transcriptional profiling, gene expression


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Lung cancer is the leading cause of cancer deaths in the industrialized world [1]. In the United States, since 1950 the age-adjusted rate (AAR) of lung cancer has increased significantly (30%) for all sexes and races, with the greatest rise (70%) in women, compared to 17% in men [2]. The changes in the AAR reflect an increase in the diagnosis and histological classification of adenocarcinoma as the presenting tumor and a concomitant decrease of squamous cell carcinoma in men. Within the classification of adenocarcinoma, the occurrence of a unique form, bronchioloalveolar carcinoma (BAC), appears to be increasing up to 3-fold [3–5] and now accounts for 2–14% of all pulmonary malignancies [6,7]. BAC is not linked to smoking, is found disproportionately in women [8–10], and has an earlier age of onset than conventional pulmonary adenocarcinoma [11,12]. These observations suggest that BAC may have an infectious origin [13].

We have used oligonucleotide microarray analysis to look at 3 paired RNA samples (normal lung tissue and pathologically diagnosed BAC tumor tissue from the same patient) in order to characterize the changes of gene expression patterns in BAC tumors, including activation and inhibition of cellular growth. Gene profiling by microarray analysis is a technically powerful approach to the clinical diagnosis and management of cancers and other diseases [14,15]. The identification and characterization of altered cellular expression in response to genetic changes, diseases, and environmental insults can provide a blueprint for the disease process. Microarray and gene-profiling methods, used in conjunction with traditional diagnostic techniques, could refine cancer diagnosis in respect to (1) classification, (2) biological staging, (3) risk assessment, (4) tracking of metastases, and (5) monitoring chemotherapy for individual tumors. Implementing this approach may improve patient management, clarity of diagnosis, prognosis assessment, and development of therapeutic agents [14–16]. In addition, transcriptional profiling of BAC may help to identify environmental factors, other than smoking, in the etiology of these tumors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Using a research protocol approved by the institution’s Internal Review Board (IRB), we isolated total RNA from sets of paired pathologic discards of resected normal lung tissue and tumor from 3 patients with the BAC form of lung cancer. Under the IRB provisions concerning pathological discards, the investigators were denied access to patient identifiers or clinical data, such as sex, age, or smoking history.

Transcriptional profiling studies of BAC were performed using Affymetrix oligonucleotide micro-arrays (Affymetrix Inc., Santa Clara, CA). These arrays are generated by attaching 107 copies of each of a predetermined set of oligonucleotides at designated locations on a solid support called a chip. Each gene is represented by 20 different oligos dispersed throughout the chip and each oligo is paired with a duplicate oligo containing a central mismatched base. The probe redundancy and mismatch controls greatly reduce the number of false positives.

Total RNA was isolated from 3 paired tumor and normal lung tissue sets by the "TRIzol" technique (Gibco BRL, Inc., Grand Island, NY) using reagents and procedures recommended by Affymetrix, Inc. Total RNA (10–20 µg from each sample) was used to generate first-strand cDNA (SuperScript Double-Stranded cDNA Synthesis Kit, Gibco BRL, Grand Island, NY), using a T-7-linked oligo-dT primer (Genset Corp., La Jolla, CA). Following the synthesis of the second strand, linear amplification of RNA was performed by incorporating biotinylated UTP and CTP by an in vitro transcription reaction (Bioarray High Yield Transcript Labeling Kit, Enzo Biochem, Inc., New York, NY).

The labeled target was fragmented to 50–150 nts size according to the procedures recommended by Affymetrix for overnight hybridization of biotinylated cRNA to their genearray chip. Each sample was hybridized to a Affymetrix HG_U95A GeneChip, which contains 12,000 known genes and ESTs (expressed sequence tags). The chips were stained with strepavidin-phycoerycoerythrin (Molecular Probes Inc., Eugene, OR), washed using the Affymetrix automated fluidics chamber, and scanned on an Affymetrix laser confocal scanner. Intensity values were scaled so the overall intensity for each chip of the same type was equivalent.

The sample data were analyzed using the Affymetrix "Microsuite 4" software package. Intensity for each feature of the array was determined as a single raw expression level for a gene, predicated upon the signal from the 20 probe pairs representing each gene. This was achieved using a trimmed mean algorithm (a fast structure-adaptive algorithm for noise reduction in images designed to allow noise to be filtered out without damaging the original image). A threshold of 20 units was assigned to any gene with a calculated expression level below 20, since the discrimination of gene expression below this level could not be performed with confidence.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
The gene profile for each paired tumor and normal lung sample was determined by comparison analysis using the normal sample as the baseline. Each individual tumor sample was compared to its normal counterpart from the same patient [17], unlike the pooling of cell lines used as a reference in a variety of studies [18–20], and the relative increase or decrease of gene expression was derived for each pair.

Variations of gene expression were noted among the tumor samples with different sets of genes showing different expression patterns, which may reflect differences in an individual tumor’s character or response. To determine if there were any genes whose expression was clearly modified in all 3 BAC tumors, the data were aligned and sorted based on fold-change.

Fourteen genes that were substantially over-expressed in all 3 BAC tumors are listed in Table 1Go. Twelve of these genes were upregulated in all 3 tumors by >=2-fold, and 6 were upregulated by >=6-fold, compared to the paired sample of normal lung tissue. These included two osteopontin genes, and the genes for intestinal trefoil factor, secreted cement gland protein XAG-2, CD4-signal transducer, and Krüppel-related zinc finger protein.


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  		Table 1. Genes that were consistently overexpressed in 3 bronchioloalveolar carcinomas, based on paired comparisons of the RNA expression levels in tumor tissue (T) with the baseline data for normal lung tissue (N) from the same patient. The results are stated as fold-changes from baseline (T/N).
 
Fourteen genes that were substantially downregulated in all 3 BAC tumors are listed in Table 2Go, including 6 genes downregulated to <= 20%, compared to the paired sample of normal lung tissue. These included genes for TSC403 protein, human receptor for RAGE, G protein-coupled receptor kinase, carboxylesterase, IL-10 receptor, and actin-binding protein p57.


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  		Table 2. Genes that were consistently repressed or under-expressed in 3 bronchioloalveolar carcinomas, based on paired comparisons of the RNA expression levels in tumor tissue (T) with the baseline data for normal lung tissue (N) from the same patient. Each result is stated as a decimal fraction of the baseline expression (T/N).
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
We have examined and compared the genetic expression in 3 paired samples of normal lung tissue and BAC tumors, and have identified several genes that were over-expressed in all 3 tumor samples and other genes that were repressed in all 3 tumor samples. Some of the genes that were over-expressed encode proteins involved in DNA binding (Krüppel zinc finger protein), transcriptional regulation (X-box binding protein), signaling (MAP kinase phosphatase, beta catenin), and cell adhesion (E-cadherin). Upregulation of E-cadherin and the catenins alpha and beta in BAC tumors, compared to conventional pulmonary adenocarcinomas, was documented previously by immunohistochemical detection [21]. Our findings agree with the protein expression study and add weight to the potential use of transcriptional profiling as a diagnostic test.

Two osteopontin genes, which were highly expressed in all 3 tumors, encode a phosphoprotein that is secreted and strongly associated with the process of neoplastic transformation. Osteopontin is required for maximal transformation by ras and has been implicated as an important effector in the ras oncogene transforming program [22]. In addition osteopontin has been identified as a growth and migration or metastasis formation marker on rat C6 glioma cells [23]. Engagement of this molecule by the CD44 homing receptor expressed on primary brain tumors and metastases evidently induces macrophage chemotaxis and may help in tumor dissemination [24].

Peptide domains of the trefoil factor family are associated with mucin-secreting epithelial cells and are synthesized predominately in the gastrointestinal tract. This family of proteins appears to be involved in mucosal defense and healing; a tumor suppressor function has also been postulated. Trefoil protein expression has been noted in various tumors, including breast and lung, where it may have some prognostic significance [25]. The functional properties of mucosal protection and injury repair are effected through coordinated activation of migration and inhibition of apoptosis [26]. The later effect involves signaling through both the EGF-R and the P13K-Akt pathways [27–29]. Turning on the expression of genes involved in migration and growth, while inhibiting the expression of those involved in cell death and apoptosis, offers an effective survival strategy for retroviral infected or tumorigenic cells.

Although they are not included in the list of upregulated genes, we observed increased expression of 2 separate genes for mucin. One of the gene products is polymorphic epithelial mucin which is develop-mentally regulated and aberrantly expressed in tumors [30]. One of the 3 BAC tumors expressed 10-fold greater amounts of this gene than the others, suggesting that this tumor may be a subtype of BAC, a mucin producing tumor with a less favorable prognosis. Consistency of such findings between microarray and histopathologic examinations of BAC tumors may corroborate the validity of transcriptional analysis of BAC.

At first glance, the genes that appeared to be downregulated in the 3 paired BAC samples serve diverse and manifest myriad functions. Among the losses of expression is the gene for PECAM-1, a member of the immunoglobin superfamily of cell adhesion molecules. PECAM-1 is a negative regulator of antigen receptor signaling and has been found to modulate a range of endothelial processes, including leukocyte transmigration, angiogenesis, migration, and monolayer permeability. PECAM-1 has functional immunoreceptor tyrosine-based inhibitory motifs within its cytoplasmic domain and acts in a coordinated fashion with cell proteins (tyrosine kinases and phosphatases among them) to trigger a variety of signal cascades integral to the physiologic activities of the endothelium [31,32].

The expression of STAF50, an interferon-induced factor that represses retroviral LTR expression, is down-regulated, consistent with the effects of retroviral infection, where viral genes are known to inhibit host genes that interfere with their expression [33].

The expression of TGF-ß IIR is also significantly repressed in these tumor cells. The anti-proliferative effect of TGF-ß signaling is therefore ablated, allowing increased cell division and expansion of the tumor cell population [34]. Though TGF-ß also establishes an immunosuppressive state, in concert with diminished expression of other modulating cytokines its signaling pathway may be rendered inactive. For example, IL-7 receptor is also downregulated, and signaling through the IL-7 receptor is required for normal T cell and B cell development and is essential for the production of TCR lineage cells. The IL-7 receptor initiates multiple signaling pathways through several non-receptor kinases that associate with the cytoplasmic tail of the IL-7 receptor chain.

NRGN is a postsynaptic protein believed to be involved in the regulation of intracellular Ca2+ and calmodulin levels after neuronal excitation. The downregulation of NRGN results in a release from inhibition of signaling events. As Ca2+/calmodulin play a central role in controlling a surfeit of cellular events, suppression of NRGN could affect diverse signaling pathways [35].

The actin-binding protein p57, which has significant homology to the coronin family of proteins, is a cyclin-dependant kinase inhibitor. The loss of p57 in podocytes releases the growth arrest of the mature cell, leads to the expression of cyclin A, and is associated with the activation of podocyte proliferation in collapsing glomerulopathies [36].

QKI-7, a member of a group of evolutionary conserved regulatory genes in the STAR family, is a translational repressor that acts through regulatory elements, called TGEs, and is essential for embryogenesis and germ cell fate [37].

The connections among these genes are the roles of their products in governing the processes leading to cell differentiation and maturation, inhibition of a proliferative state, or growth arrest. These processes are crucial to releasing the tightly regulated blocks on transcriptional activation and translation. By suppressing genes that inhibit specific signal transduction cascades, cells may be permitted to enter the cell cycle and proliferate. Collectively, these findings may support our hypothesis of an environmental etiology for BAC, other than smoking.

A comparison of the gene profiles obtained with subtractive hybridization clones from a normal and a metastasizing lung adenocarcinoma cell line [38] and the results of this study did not reveal any similar patterns or common up- or downregulated genes. This includes the genes from regions of chromosomes such as 6q21 [PDB] (AIM1), which are frequently deleted in lung cancer and are unchanged in BAC. Additionally, there was no apparent correlation with the regions of chromosomes that are altered and amplified in lung and other solid tumors, contributing to instability and transformation. We looked for loss of tumor suppressors (eg, p53 and PTEN) in the BAC samples, but there were no changes in the expression levels of these regulatory genes. This contrasts with the findings in numerous studies of progression to lung cancer. As with the pathological and metastatic findings for BAC, the gene expression patterns suggest that these tumors may have a different etiology than typical bronchiogenic cancers.

It should be noted that Table 2Go does not include any of the identified ESTs that were downregulated. Of the 9 genes with most suppression of expression in the BAC samples, 3 were ESTs. This intriguing finding suggests the potential for novel gene discovery, possibly elucidating the function of those genes and offering new diagnostic markers or therapeutic targets for BAC tumors.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors thank Milka Rodriguez for expert technical assistance. This work was supported by funds from the Molecular Genetics Laboratory and a gift from Theodore Danforth (for establishing the microarray facility) of the North Shore-Long Island Jewish Research Institute. The laboratory and investigators have no potential conflicts of interest; there was no corporate support for this study.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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