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Department of Pathology and Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York
Correspondence and requests for reprints should be addressed to Dr. Charles A. Powell, Division of Pulmonary and Critical Care Medicine, Columbia University Medical Center, 630 West 168th Street, Box 91, New York, NY 10032. E-mail: cap6{at}columbia.edu
ABSTRACT
Recent lung cancer research has been directed to using molecular approaches to facilitate early diagnosis, to identify clinically relevant biological factors associated with histologic heterogeneity, and to identify novel therapeutic agents. This research takes advantage of technical advances that allow rapid high throughput assays to interrogate the genome, proteome, and epigenome. In this review of gene expression profiling in lung carcinogenesis, we will focus upon recent advances in the understanding of malignant transformation of lung epithelial cells and of lung cancer differentiation and progression. These studies have provided important information about the genomic alterations of tobacco smoke–associated airway field carcinogenesis and about the developmental pathways that mediate lung tumor invasion and histologic differentiation in response to injury.
Key Words: adenocarcinoma • gene expression • growth and development • smoking
Lung cancer is the leading cause of cancer death in the United States, with 162,000 deaths expected in 2006 (1). However, lung cancer incidence is fourth, less common than breast, colorectal, and prostate carcinoma. In fact, the sum total of deaths attributable to these three more common cancers does not exceed the number of deaths attributable to lung cancer. The disparity in mortality is illustrated by the three-decade trend in five-year survival rates. Prostate, breast, and colorectal carcinoma have all demonstrated significant improvements in five-year survival over time and are currently 99, 88, and 64%, respectively. In contrast, the survival rate for lung cancer trend remains relatively flat and is currently 15%.
There are several potential explanations for the disparity between lung cancer survival and that of the more common tumors. These explanations include late detection and histologic heterogeneity. Currently, over 75% of new lung cancer diagnoses are in patients presenting with distant or regional metastatic disease (1). This rate is markedly higher than that of breast, colon, and prostate cancer, for which there are approved screening programs. In contrast, there is no approved screening program for lung cancer. Encouraging recent reports suggest that screening with low-dose chest CT may provide a clinical benefit; however, other reports suggest that over-diagnosis bias may limit the overall utility of the procedure (2). Histologically, prostate, breast, and colorectal carcinomas are uniformly adenocarcinoma and treatment is primarily determined by clinical stage, at times modified by results of molecular assays (3, 4). In contrast, adenocarcinoma comprises only 30% of lung carcinoma, yet for the most part non–small cell lung cancers (squamous, large cell, adenocarcinoma) are treated similarly, regardless of the biological heterogeneity associated with histology. It is likely that poor lung cancer response rates may in part be attributable to suboptimal targeting of therapeutics. Future refinement of treatment strategies that allocate treatment based upon unique biological properties of tumors, as exemplified by targeting of tyrosine kinase inhibitor to tumors harboring epidermal growth factor receptor alterations (5, 6), may improve response rates and mortality rates.
Recent research has been directed to using molecular approaches to facilitate early diagnosis, identify clinically relevant biological factors associated with histologic heterogeneity, and identify novel therapeutic agents. This research takes advantage of technical advances that allow rapid high-throughput assays to interrogate the genome, proteome, and epigenome. In this review of gene expression profiling in lung carcinogenesis, we will focus upon recent advances in the understanding of malignant transformation of lung epithelial cells and in lung cancer differentiation and progression. These advances have direct relevance to the goals of early detection, accurate prognostic assessment, and targeted therapy.
FIELD CARCINOGENESIS
Cigarette smoking causes lung cancer. Fifteen percent of lifetime smokers develop lung cancer, and approximately 10% of lung cancer cases arise in never-smokers (7). In nonsmokers, exposure to second-hand smoke or to other lung carcinogens such as radon, asbestos, arsenic, or air pollution may be contributory. In smokers, genetic susceptibility factors associated with carcinogen metabolism, DNA damage repair, and cell cycle control are important in modifying the injury response to exposure of the dozens of carcinogens contained in tobacco smoke exposure (8). In smokers, the ubiquitous response to smoke exposure is field cancerization of the bronchial epithelium in which airway cell DNA is altered. These alterations result in oncogene activation, tumor suppressor gene silencing, and widespread loss of heterozygosity (LOH), all of which drive distinct gene expression signatures. In some instances, field carcinogenesis culminates in malignant transformation of lung cancer progenitor cells, yet it is unclear which molecular alterations in the field carcinogenesis cascade are sufficient. In addition, it is unclear if the malignant transformation of the epithelial field alterations requires contribution from other systemic cell types, such as bone marrow–derived stem cells (9).
Microarray expression profiling has provided important information about cigarette smoking–associated lung carcinogenesis. Recently, we and others have used gene expression profiling to identify gene signatures associated with cigarette smoking and lung adenocarcinoma in smokers and nonsmokers (10). Unsupervised hierarchical clustering analysis demonstrated that the nonmalignant lung specimens of smokers clustered separately from those of nonsmokers. In addition, four times as many genes changed expression in the transition from noninvolved lung to tumor in nonsmokers as in smokers. Together, these results suggest that adenocarcinoma in smokers and nonsmokers involve different pathways of cell transformation and different stromal tissue responses. In smokers, adenocarcinoma arises in a field of genetically altered lung tissue, while in nonsmokers it arises locally in a field of relatively normal lung tissue, thus providing genomic corroboration of field carcinogenesis.
Interestingly, in this study and in that of Miura and coworkers (11), tumors did not segregate according to smoking status. In light of recent reports indicating preferential activation of the Kras pathway in tumors of smokers and of the epidermal growth factor receptor pathway in nonsmokers (12), this result suggests that the number of tumors examined in the profiling studies was too small to detect clustering associated with pathway activation and with smoking status.
Interestingly, in the studies of both Miura and colleagues and Powell and coworkers, supervised analyses of genes differentially expressed in tumors of smokers and nonsmokers identified gene clusters within chromosomal loci (3p21, 3p14) that frequently demonstrate LOH in smokers (11, 13, 14). This supports the complementary nature of information provided by gene expression profiling and by other methods of genomic analysis such as LOH analysis, copy number analysis, and methylation profiling, and additionally suggests that the DNA alterations of cigarette smoke–associated field carcinogenesis in the airways of smokers persist within tumors.
Additional insights into the molecular signatures associated with airway exposure to cigarette smoke were provided by a series of observational studies performed using a microarray analysis of bronchial epithelial cells obtained from bronchoscopic brushings of healthy smokers and nonsmokers (15, 16). Gene ontologies overexpressed in cells of smokers were predominantly xenobiotic metabolism and antioxidants; however, these changes appeared to be potentially reversible when evaluated in a comparison of current versus former smokers. The transient genomic response to injury has been confirmed by in vitro studies using human bronchial epithelial cells exposed to cigarettes smoke condensate and by in vivo models of rodent exposure to cigarette smoke (17). The persistent genomic response to smoke remains unclear, but genes altered similarly in current and former smokers, as noted in the study by Spira and colleagues, may provide insights (16).
Both the "macro"-analysis of global gene expression signatures and the "micro"-analysis of specific differentially expressed genes in lung carcinogenesis have been informative. For example, within the adenocarcinoma smoking dataset (10), specific genes were identified whose expression changed in the nonmalignant lung of smokers compared with nonsmokers; these alterations, many of which involve genes important in embryologic lung development, might represent early events in the multistep progression toward lung cancer. Kim and colleagues identified GPC3 (chromosome Xq26), which encodes the heparin sulfate proteoglycan Glypican 3 that regulates growth during normal development, as having lower expression in tumors compared with nonmalignant lung and lower expression in the nonmalignant lungs of smokers compared with nonsmokers (18). This suggested GPC3 is a potential lung tumor suppressor gene regulated in part by exposure to cigarette smoke carcinogens. Kaplan and coworkers identified H19, a paternally imprinted gene (which, similar to GPC3, has regulator functions in development and carcinogenesis), as being monoallelically upregulated in the airways of smokers (19). Therefore gene signatures and specific genes that have functions in normal development are implicated as having similar importance in mediating the response of the airway epithelium to carcinogen exposure and injury.
The effects of cigarette smoke are not restricted to conducting airway epithelial cells, but are also detectable in alveolar macrophages and in peripheral leukocytes. For example, polycyclic aromatic hydrocarbon (PAH) DNA adducts are detectable in the peripheral leukocytes of smokers and are associated with risk for lung carcinoma (20). Similar to prior observations using bronchial epithelial cells, Heguy and colleagues detected increased expression of antioxidant-related genes and chemokines and chemokine receptors associated with inflammation in alveolar macrophages of smokers (21). In a study of peripheral leukocyte expression profiles, Lampe and associates identified a gene signature that correlated with plasma cotinine levels and was predictive of smoking status (22). This peripheral blood–based signature of smoke exposure holds promise as a noninvasive biomarker of cigarette smoke effects and provides information regarding the role of the systemic response to local lung inflammation in the development of disease. Taken together, these studies identify a local and systemic gene expression response to cigarette smoke exposure, and they highlight the inter-individual variability in these responses that potentially parallel inter-individual differences in susceptibility to smoking-associated diseases such as lung cancer and chronic obstructive pulmonary disease. Studies to prospectively correlate airway cell gene expression biomarkers with subsequent development of disease will be required to confirm this hypothesis.
A limitation of observational studies of smoking effects on the lung is that smoke exposure is a chronic condition that is typically associated with other exposures; thus the causality of smoking on gene expression profiles is presumed but not confirmed. Recent research employing gene expression profiling of genetic models of lung cancer and smoke-exposed animals have reduced confounding by the above factors and provided important information. Several murine lung tumor models have been developed over the years that include treatment-induced models and, more recently, genetic models. In addition to cigarette smoke models that deliver complex mixtures of carcinogens, other frequently used models directly deliver single carcinogens such as NNK, Benzo-(a)-pyrene,N-ethyl-N-nitrosourea (ENU), and urethane (23) delivered by intraperitoneal and/or gastric routes. Although cigarette smoke exposure models may closely parallel carcinogen exposure in humans, our experience and that of others shows that tumor incidence is low, and that tumors occur at unpredictable time points and are uniformly noninvasive (24, 25). In contrast, NNK and urethane exposure models are more similar to human tumors histologically and genomically (26, 27).
There are a number of recently developed genetic models of lung cancer, such as the transgenic oncogenic mutated Kras2 mouse and the Kras/p53 compound conditional mutant models, that have distinct advantages (28–31), including reproducibility, the ability to control the number and sizes of tumors, and an aggressive phenotype in the compound model that is similar to metastasis in human tumors. Genomic analysis of tumors in oncogenic Kras animals indicates that the molecular profiles of these tumors are more similar to human adenocarcinomas than to morphologically similar tumors produced in the NNK exposure model (32). Thus, important roles for expression profiling in these models are to validate the generalizabilty to human lung cancer as well as to identify the activated downstream pathways in response to carcinogen exposure or to mutation events.
Expression profiling using DNA microarrays has identified hundreds of genes differentially expressed in human lung tumors compared with nonneoplastic tissue (33, 34), yet it remains difficult to determine which genes are required for cancer and which represent epiphenomenon. Rhodes and coworkers performed a meta-analysis of expression profiles generated from dozens of cancer microarray studies in several tumor types to identify a gene signature of cancer relative to normal tissue (35). This tumor "meta-signature" contained genes involved in the cell cycle, transcriptional regulation, protein folding, and the proteasome; the commonality of this shared signature suggests that these genes play important roles in tumorigenesis. Recent research has been directed to understanding the subsequent steps of tumor differentiation and progression.
HISTOLOGIC HETEROGENEITY
Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histologic cell types. These paradigms suggest that lung tumor cell ontology is determined by the consequences of gene transcriptional activation and/or repression events that recapitulate events important in embryonic lung development (36). This hypothesis is supported by studies demonstrating correlations between human lung tumor gene signatures and signatures of normal lung development (26, 37). This developmental perspective has provided important insights into investigations implicating specific progenitor cells for lung carcinoma subtypes.
Neuroendocrine Tumors
In one of the first studies using gene expression profiling to examine lung cancer histologic diversity, carcinoids and small cell carcinomas (SCLC) (38) were compared. Although a limited sample, the carcinoids clustered with gliomas, while the small cell carcinomas clustered with bronchial epithelium. This suggested that SCLC arise from bronchial epithelium, while carcinoids, despite having neuroendocrine differentiation in common with SCLC, bear more similarity to gliomas. Since glial cells are of neural crest origin, this suggested that carcinoid tumors but not SCLC arise from neural crest–derived pulmonary neuroendocrine cells.
The observation that carcinoid and small cell carcinomas represent distinct molecular subgroups is supported by subsequent studies. Bhattacharjee and colleagues (33) found two distinct clusters of small cell carcinomas and carcinoid tumors, with SCLC characterized by frequent expression of proliferation markers such as MCM2, PCNA, MCM6, and thymidylate synthase. This was confirmed by Jones and coworkers (39), who identified a distinct carcinoid subgroup that was separable from high-grade neuroendocrine carcinomas. Interestingly, large cell neuroendocrine carcinoma, which is a high-grade neuroendocrine carcinoma classified as a non–small cell carcinoma (NSCLC), was not readily distinguishable from SCLC by gene expression profiling. Among the genes with increased expression in large cell neuroendocrine carcinoma shared with small cell carcinoma were cell cycle related and DNA replication genes including MCM genes (MCM3, -4, and -6) and thymidylate synthase.
The phenotype of high-grade neuroendocrine tumors may be driven by the Achaete-scute homolog 1 (ASCL1) transcription factor. Linnoila and colleagues crossed transgenic mice with ASCL1 overexpression in Clara cell–specific cells with SV40 large T antigen transgenic mice and observed a phenotype of large cell neuroendocrine carcinomas (40). Subsequent studies of high grade neuroendocrine carcinomas by gene expression profiling have found ASCL1 to be important in distinguishing SCLC from carcinoid (33).
Nonneuroendocrine Carcinoma
Studies of nonneuroendocrine carcinomas have also found differences between histologic high- and low-grade carcinomas. Garber and associates (34) studied 67 lung tumors, 4 of which were large cell carcinoma (LCC), a high grade undifferentiated non–small cell carcinoma. Three LCC clustered in a group of six tumors that included three AdCas. The remaining LCC clustered in a subgroup of AdCas. Interestingly, the LCC group clustered with the SCLC group. Perhaps of greater interest was reduced expression of cell adhesion related genes in high-grade LCC; such a step may be necessary in the acquisition of a motile phenotype of invasion and metastasis. These clustering data also suggested that LCCs share similarities with AdCas. A similar pattern was identified by Takeuchi and coworkers in a gene expression profiling study of 149 NSCLCs (including 18 LCC), which showed a distinct LCC cluster with 13 of 18 LCCs grouping together. Of the other LCC tumors, all five were within the AdCa group (41).
The overlap of large cell carcinoma expression profiles with those of adenocarcinoma subsets are of interest when applied to studies focused on adenocarcinoma heterogeneity. Several adenocarcinoma expression profiling studies have observed three or four subgroups using unsupervised hierarchical clustering (10, 33, 34). Analysis of the adenocarcinoma dataset from the study by Bhattacharjee and colleagues showed 139 AdCas divided into four clusters by unsupervised clustering. Closer examination of the groups showed one cluster (C1) of poorly differentiated AdCas associated with increased expression of cell cycle–related genes. The second cluster (C2) showed neuroendocrine differentiation and was associated with poor prognosis. The third and fourth clusters (C3,C4) were comprised of well-differentiated tumors that expressed genes related to type II cells (TTF1, MUC1, and surfactant genes) and normal lung. These two clusters contained all the bronchoalveolar carcinomas (BAC), with the fourth group containing the majority of the BACs.
In an analysis of 25 adenocarcinomas, Borczuk and associates identified three groups that were similar to those reported by Bhattacharhee and coworkers. The tumors were comprised of adenocarcinoma subtypes ranging from low-grade BAC to high-grade pure invasive tumors, which are representative of histologic subtypes in the progression of invasion (43). Invasion is the first step of the metastasis process, in which epithelial cells lose cell–cell adhesion, gain motility, and invade into adjacent stroma. Subsequent steps of metastasis include tumor cell intravasation into blood vessels, extravasation at distant sites, and proliferation (44). Hierarchical clustering indicated that the tumors clustered according to histologic subtype. Cluster 1 contained adenocarcinomas with poor differentiation, cluster 2 contained mixed subtype adenocarcinomas with a BAC pattern, and cluster 3 contained the BAC type tumors. These clusters were similar to Bhattacharjee clusters 1, 3, and 4. Importantly, decreased expression of transforming growth factor receptor II (TGFßRII) was associated with increased invasiveness in these adenocarcinomas, suggesting that deregulation of TGF-ß signaling is an important determinant of lung adenocarcinoma progression and clinical outcome.
Takeuchi and colleagues examined 90 adenocarcinomas of lung and determined two primary clusters of tumors described as terminal respiratory unit (TRU)- and non–TRU-type adenocarcinomas (41). TRU carcinomas were histologically well differentiated and showed type II cell differentiation (i.e., TTF1 expression) and could be separated into BAC-type tumors (TRU-b) and non–BAC-type tumors. EGFR mutations occurred with greater frequency in TRU than non-TRU tumors, and K-ras mutations were not seen in the less invasive TRU-b subgroup.
Together, these studies suggest that the development of adenocarcinoma may follow two distinct paths. In one path, tumors that show TRU (Clara cell or type II) differentiation progress from noninvasive BAC to increasingly invasive mixed subtype adenocarcinomas, perhaps as a result of TGFßRII repression. The second path culminates in tumors that are poorly differentiated with no evidence of BAC pattern. These poorly differentiated tumors frequently overexpress genes with functional categories of the cell cycle and DNA replication control, as seen in large cell carcinoma. The molecular parallels of poorly differentiated high-grade adenocarcinoma subsets with large cell carcinoma raises important issues regarding tumor ontogeny. Whether these two adenocarcinoma progression paths derive from different progenitor cells (proximal versus distal airway), or from differentiation arrest of a common progenitor at different stages of maturation, remains unclear.
The clinical relevance of adenocarcinoma differentiation profiling is supported by studies such as that of Beer and coworkers that have identified signatures of adenocarcinoma prognosis (42). Similar to adenocarcinoma studies described above, the tumors clustered into three groups, with a poorly differentiated cluster containing the largest proportion of Stage III tumors, and a well-differentiated cluster showing the closest relationship to normal lung. Tumors with BAC histology were present in two of the three clusters, with 35% of their well-differentiated cluster containing BAC pattern tumors. The main focus of their study was to develop a gene predictor of survival on their samples and test it an independent set of 84 tumors. This 50-gene predictor, which contained many genes important in lung differentiation and cell cycle control, could separate Stage I lung adenocarcinoma into high- and low-risk survival groups, which importantly was validated in an independent dataset. Similarly, Potti and colleagues reported a signature of metagenes that were predictive of recurrence in stage I non–small cell lung carcinoma (45). These metagenes were comprised of several genes representative of lung development and proliferation pathways, further supporting the association of these ontologies with lung cancer progression.
LUNG DEVELOPMENTAL PATHWAYS IN LUNG CANCER
In an analysis of 32 non–small cell lung carcinoma specimens and 7 normal specimens (37), unsupervised clustering separated tumors on the basis of histologic type and differentiation. Normal samples and carcinoid tumors showed distinct clusters. Of the four LCCs studied, three clustered together with one AdCa and the fourth clustered in a group of AdCas. Genes that were overexpressed in these LCC-related clusters included a preponderance of cell cycle genes, DNA replication–related genes, and transcription factors. Specifically, E2F3 was identified, as was MYBL2, an E2F-regulated gene. Other cell cycle–associated genes included BUB3, CDK4, and MCM2, MCM3, and MCM7. Several of the proteins encoded by genes identified in supervised clustering are important in embryonic lung development. We hypothesized that molecular signatures associated with tumor histologic classes were representative of gene expression during lung development, as manifest by temporal signatures according to embryonic stage or by spatial signatures according to cell location (peripheral, proximal) or by cell of origin (epithelial, mesenchymal). To examine the association of lung tumor histologic gene markers sets with temporal stages of lung development, we used gene expression data previously generated from murine lungs obtained serially from Embryonic Day 12 through adult. Comparison of the histology classifiers with genes that are temporally activated during mouse lung development revealed that genes expressed by LCC were expressed during the early pseudoglandular and canalicular stages of lung development, while those expressed by AdCa were expressed during the later terminal sac and alveolar stage of lung development. In addition to highlighting the proliferation-associated genes in LCC and differentiation-associated genes in AdCa, this suggested that these tumors may be recapitulating developmentally regulated pathways.
Similarly, in a study of normal mouse lung, adenomas, and adenocarcinomas, Bonner and associates (26) compared gene expression in murine tissues to expression in human lung tumors. Tumors showed a decrease in apoptosis-related genes (MDA5), in cell cycle control genes, in APC2, an increase in a tyrosine kinase (ROS1), and an increase in DNA replication–associated genes. In the transition from adenoma to carcinoma, there was a decrease in differentiation-associated genes (WNT6 and homeobox C6) and an increase in ETS2, NTF2 (nuclear importer of oncogenic RAS), cell cycle–related genes, and ADAM10 (a migration factor). A focus on lung development–related genes identified three genes that were increased in early development, decreased in adult lung, and re-expressed in tumors. These genes included CDC5 (cell cycle), MOK2 (zinc finger transcription factor), and ubiquitin-binding protein A (protein degradation). A comparison of murine tumors with human lung cancers identified 39 common genes. In this shared signature set, metabolism-associated genes were decreased and those related to the cell cycle (cdk4, cdc2), anti-apoptosis (bcl7b), and the proteasome were increased. By clustering analysis, human lung AdCas clustered with mouse adenomas, while LCCs and a subset of human AdCa clustered with mouse lung adenocarcinomas.
Extending the work on the relationship between lung development and lung cancer histology, Liu and coworkers (46), using the Bhattacharjee gene expression dataset, found that genes associated with early lung development were more often expressed in SCLC. In addition, genes associated with early lung development were more often seen in tumors with poorer prognosis. Included among their 100 genes associated with early lung development and poor prognosis were several of the cell cycle/DNA replication–related genes previously described in classifiers of small cell carcinoma (PTTG1 [47], MCM2, and MCM6 [33]), large cell carcinoma (MCM7, MCM2, MCM3 [10]) and both SCLC and LCC (DNA topoisomerase2a [45]). This suggests that poorly differentiated histology and molecular parameters of early development are linked and that gene signatures of these phenotypes are important for lung cancer progression and are potential biomarkers of clinical outcome (48).
Recent studies have provided important information regarding specific lung developmental pathways such as sonic hedgehog that may be important for lung tumor differentiation and progression (49). Shh ligand production by epithelia is important in lung development, playing a role in branching morphogenesis. Using an airway injury model, Watkins and associates observed that the Hh pathway was required for neuroendocrine cell differentiation and was also required for small cell lung cancer growth. These results suggest SCLC may arise from injury to an airway epithelial progenitor cell under control of Hh signaling.
Taken together, these observations associate lung tumor differentiation states and histologic grade with epithelial cell developmental pathway molecular signatures. These findings suggest that histologic diversity in lung carcinomas reflects various degrees of differentiation arrest from a common progenitor cell. Undifferentiated high-grade tumor molecular profiles are comprised predominantly of cell cycle–related and transcription regulation genes, whereas lower-grade tumor signatures are comprised of genes representative of terminal differentiation pathways.
Such observations have precedent in tumors of hematopoietic origin. In lymphoid tumors, the classification schema mirrors different stages of lymphoid maturation, which are in turn associated with specific gene expression profiles. These neoplastic cells often bear histologic and cell surface marker correlation with known stages of B cell maturation. For example, the recognition of patterns of somatic hypermutation in diffuse large B-cell lymphoma (DLBCL) suggested germinal center B cell differentiation (50). By focusing on genes related to germinal center maturation, two groups of DLBCL could be determined based on germinal center type gene expression and activated peripheral B cell–like phenotype. This was of prognostic significance, as the germinal center-like DLBCL had better prognosis (51). This has led to speculation that the process of somatic hypermutation may play a critical role in the pathogenesis of DLBCL (52).
If this paradigm in lymphoid tumors extends to the lung, study of epithelial cell maturation states may identify distinct sets of transcriptionally regulated programs activated by epithelial cell injury. As illustrated by Watkins and coworkers (49), airway injury and tumors recapitulated Hh pathway programs of lung development, perhaps representing the phenotype of small cell carcinoma. Therefore, it may be that each of the WHO classes of lung carcinomas reflects an as yet unrecognized epithelial cell developmental phenotype that is perhaps re-expressed in lung injury. If this is the case, further analysis of epithelial cells in the setting of lung development and airway injury may reveal previously undescribed stages of lung epithelial cell differentiation much like the somatic hypermutation pattern detected in lymphoid maturation. This paradigm suggests that high-grade lung tumors such as large cell carcinoma harbor profiles associated with arrest at a stage closer to the undifferentiated progenitor cell. Further, it suggests that adenocarcinoma retains the ability to differentiate and that the commitment to low-grade terminally differentiated states versus high-grade poorly differentiated states is dictated by developmentally important gene expression programs. While speculative, these observations warrant future study directed to identifying the expression profiles associated with the specific epithelial response to injury and the relationship to carcinogenesis.
Expression profiling of lung cancer development has provided important information about genomic alterations associated with tobacco smoke field carcinogenesis and about the pathways mediating lung tumor differentiation and progression. Future directions of expression profiling include studies directed to examining the molecular profiles of lung cancer precursor lesions such as squamous carcinoma in situ, atypical adenomatous hyperplasia, and diffuse neuroendocrine cell hyperplasia (53). Recent technical advances that allow for the acquisition of robust gene expression profiles from laser capture microdissection of small specimens have made the genomic analysis of these precursor lesions feasible. These studies should provide important information regarding the genomic correlates of field carcinogenesis progression, identify candidate early detection biomarkers, and provide additional insights into the role of developmental pathways in lung carcinogenesis.
FOOTNOTES
This study was supported by the American Cancer Society (RSG-CNE-108857), American Thoracic Society/Lungevity Foundation, and Joan's Legacy Foundation.
Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form July 15, 2006; accepted in final form September 13, 2006)
REFERENCES
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S. Dubey and C. A. Powell Update in Lung Cancer 2006 Am. J. Respir. Crit. Care Med., May 1, 2007; 175(9): 868 - 874. [Full Text] [PDF]
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