There are over one million deaths a year worldwide due to lung cancer, making it one of the most prevalent and deadly cancers in economically advanced countries. For instance, more than 170 000 deaths per year in the United States are attributed to lung cancer, while Japan is facing a dramatic increase in such deaths, which currently claim more than 50 000 lives annually. Lung cancers can be classified into two major entities based on their clinicopathologic characteristics. Small cell lung cancer (SCLC) accounts for 15–25% of lung cancers, and non-small cell lung cancer (NSCLC) for 75–85%. The latter consists of three major histologic types, i.e. adenocarcinoma, squamous cell carcinoma and large cell carcinoma. At present, no more than 15% of cases can be cured, meaning that the number of deaths remains unacceptably high. There is no doubt that cigarette smoking is the most important causative factor in the development of lung cancer, and approximately 75–85% of the cases can be attributed to it. Asbestos, radon, other occupational and environmental risk factors as well as genetic susceptibilities are thought to contribute to the rest. It is unfortunate that the last 20 years have not yielded substantial improvements in the treatment of lung cancer, but this same period has witnessed a rapid increase in the store of information concerning the molecular mechanisms which give rise to lung cancer as a result of such genetic insults.
It is important that a number of epidemiological studies have suggested that susceptibility to lung cancer may be inherited. Several lines of evidence have indicated that individuals may carry genetic differences in the activities of their carcinogen metabolism, resulting in considerable inter-individual variations in the risk of lung cancer even for the same amount of cigarettes smoked. Emerging evidence also suggests that inherited differences, or genetic polymorphisms, of certain genes expressed in the mesolimbic system of the brain may influence the risk of acquiring the smoking habit. Recent advances in the understanding of genetic susceptibility to lung cancer are summarized and discussed in depth by Shields.
Non-random chromosomal deletion and loss of heterozygosity are a hallmark of the involvement of tumor suppressor genes residing at the affected chromosomal regions, while oncogene amplification can be identified by cytogenetic findings such as homogenously staining lesions and double minutes. Previous cytogenetic studies including comparative genomic hybridization analysis have indicated that lung cancer cells frequently carry complex chromosomal changes, suggesting their significant roles in the development of lung cancer. These changes take the form of both numerical and structural aberrations. Balsara and Testa summarize the information accumulated in this important research area and discuss what the results tell us in terms of both definite and potential candidates for the molecular defects involved.
It has been suggested that chromosomal instability may contribute to carcinogenesis and tumor progression by facilitating loss of heterozygosity and consequent phenotypic manifestations of inactivated tumor suppressor genes, as well as by favoring polysomy of chromosomes harboring growth-promoting genes such as oncogenes. The persistent presence of the chromosomal instability phenotype has been shown to be a common feature for lung cancers associated with aneuploidy. This suggests that aneuploidy may be regarded as a cross-sectional view of chromosomal instability, reflecting chromosomal aberrations detected at a particular time point during tumor progression. In this connection, it is becoming increasingly clear that lung cancer cells carry impairment of multiple checkpoints of the cell cycle. The review by Masuda and Takahashi provides an overview of the possible molecular mechanisms behind such complex chromosomal aberrations in lung cancer cells.
It is now generally accepted that transformation of lung epithelial cells requires inactivation of multiple tumor suppressor genes. To date, it has been suggested that more than 10 tumor suppressor genes play a role in lung carcinogenesis. Since the identification of p53 mutations in 1989, first in colon cancer and then in lung cancer, the p53 gene has attracted much attention from cancer researchers because of its frequent and prevalent alterations in virtually all human cancers. As a result, p53′s role as a guardian of the genome in the face of DNA damage has been firmly established. As for lung cancer, the p53 gene is definitely one of the most critical targets for genetic alterations, showing mutations in 80–90% of SCLC and in up to 70% of NSCLC depending on the histological types examined. The article by Robles et al. describes current understanding of how p53 mutations are introduced into the genome of lung epithelial cells as a result of genetic insults caused by exposure to cigarette smoke and how the outcome, i.e. p53 inactivation, may affect the multi-step process of lung carcinogenesis from the biochemical and biological point of view.
Additional important targets for frequent genetic aberrations in lung cancer include the Rb gene at 13q14 and the p16 gene at 9p21. The Rb gene was initially cloned as a prototype tumor suppressor gene responsible for a rare childhood tumor, retinoblastoma, while among human adult cancers SCLC is a prominent and distinct example of a carcinoma carrying highly frequent Rb inactivation. In contrast to the almost consistent occurrence of Rb alterations in SCLC, Rb mutations are seen only infrequently in NSCLC. It is interesting that such tumors with normal Rb frequently suffer from epigenetic, rather than genetic, inactivation of the p16 gene due to aberrant DNA methylation of the promoter region, which constitutes another important alternative mechanism for the inactivation of tumor suppressor genes in lung carcinogenesis. Rb represses the E2F-dependent transcription important for cell cycle progression at the G1-S boundary, whereas p16 encodes an inhibitory molecule of the G1 cyclin/cyclin-dependent kinase (CDK) complexes, which efficiently inactivates Rb. Therefore, both SCLC and NSCLC appear to have distinct defects in the same crucial pathway controlling G1-S transition. This concept is discussed in detail by Kaye.
Positional cloning approaches have been successfully employed to search for as yet unidentified putative tumor suppressor genes. A clue for the presence of a tumor suppressor gene(s) on the short arm of chromosome 3 (3p) was reported as early as 1982. Since then, this chromosomal region has been the focus of intense research activities by many investigators. While ROBO1/DUTT1 at 3p12, FHIT at 3p14 and RASSF1A at 3p21.3 have been identified as targets, detailed analyses have clearly shown the existence of multiple additional candidate tumor suppressor genes on chromosome 3p. Zabarovsky et al. provide a cutting-edge overview of the 3p-tumor suppressor gene ‘saga’. Another way of cloning a putative tumor suppressor gene would involve a functional approach. A putative tumor suppressor gene at 11q23 has also been sought for many years because of the high prevalence of deletions in this chromosomal region. In this review issue, Murakami describes the rationale for and methodological details of this attractive, yet relatively uncommon strategy as well as the successful identification of a credible candidate, TSLC1.
Knowledge of specific genes undergoing either genetic or epigenetic alterations as well as of specific chromosomal regions involved in multi-step lung carcinogenesis will prove useful for early detection of cells that are destined to become malignant as well as for identifying surrogate or intermediate markers for follow-up in chemoprevention efforts. It has been shown that alterations in lung cancer-associated genes are present in the earliest form of a lesion, i.e. hyperplasia, during the evolution of lung cancer and even in epithelial cells with normal morphological appearance. McWilliams et al. provide up-to-date, extensive information about recent advances in the detection methods of early lesions in relation to current understanding of early molecular changes in the multi-step progression cascade from preneoplastic cells to fully transformed, invasive cancers. Mao describes the current state of the art and future prospects of molecular diagnosis including the minimally invasive means using sputum or serum, and discusses how we can take advantage of our rapidly growing understanding of the molecular pathogenesis to realize its clinical implementation. Perhaps the most eagerly awaited application of basic laboratory findings to the clinical environment concerns the rational development of novel therapies which target various molecules involved in the carcinogenesis and progression of lung cancers. We are indeed currently witnessing the beginning of successful attempts to transfer basic research findings to clinical applications. For example, specific inhibition of the epidermal growth factor receptor, which is often overexpressed in lung cancers, is currently undergoing clinical trials, while there are also ongoing clinical studies on specific inhibitors of the vascular endothelial growth factor receptor, a key molecule of tumor angiogenesis. Giaccone provides an overview of the rationale for, current status of and future prospects for such molecular-targeted interventions in the treatment of lung cancers.
It has been a privilege for me to assemble these reviews, which I firmly believe are successful illustrations of how much we have succeeded in recent years in obtaining a better understanding of this number one killer. I hasten to point out, however, that this issue does not intend to cover all of the related areas, and indeed many important issues such as the involvement of dominant oncogenes and the molecular mechanisms of lung cancer metastasis are not represented at all. However, the articles contributed here by outstanding researchers in the field from their unique molecular oncological points of view will surely provide the readers with comprehensive and cutting-edge information, and will hopefully stimulate new approaches aimed at conquering this extremely fatal disease.
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