Oncogenes and Antioncogenes in Lung Tumorigenesis

doi:10.1378/chest.109.5_Supplement.130S

Chest

Volume 109, Issue 5, Supplement, May 1996, Pages 130S-134S

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The role of oncogenes and antioncogenes in lung tumorigenesis is discussed in this review, with particular emphasis on their prognostic significance. Mutations in the ras family of oncogenes, overexpression of the myc and neu families of oncogenes, and mutations of p53, the recessive tumor suppressor gene, occur with differing frequencies in small cell lung cancer and non-small cell lung cancer, and are usually associated with a poor prognosis. Loss of heterozygosity, notably on chromosomes 3p, 5q, 9p, 13q, and 17p, is a common feature in lung carcinomas and its importance is also discussed.

Section snippets

Biological Markers of Lung Cancer

With the help of human lung cancer cell lines, several biological markers have been identified that enable small cell lung cancer (SCLC) cells to be distinguished from non-small cell lung cancer (NSCLC) cells.¹ Furthermore, an intermediate category of SCLC cells has been described that lacks several markers of neuroendocrine differentiation characteristic of classic SCLC cells (Table 1). Typically, SCLC cells grow in the absence of substrate adhesion, whereas NSCLC cells are attached to the

Oncogenes and Tumor Suppressor Genes Involved in Lung Cancer

The genes involved in the process of tumorigenesis are oncogenes, dominant genes, and recessive tumor suppressor genes, or antioncogenes. Oncogenes can be activated by several mechanisms, including mutation (eg, ras), and amplification or overexpression (eg, myc) of a normal cellular gene (proto-oncogene), and this may induce neoplasia;¹ inactivation of antioncogenes may also result in neoplasia. Furthermore, there is increasing evidence that both oncogenes and antioncogenes may be involved in

Conclusions

Although our understanding of the role of oncogenes and antioncogenes in the process of lung tumorigenesis is still in its infancy, genetic markers have been identified that may have a place in screening for early evidence of disease or preinvasive changes (p53), and for disease prognosis (p53, K-ras, HER-2/neu, myc). There is increasing evidence that some of these genes, such as p53 and HER-2/neu, are involved in drug resistance. This raises the possibility of their use as chemosensitivity

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Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16^INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.
Role of nuclear receptors in lung tumourigenesis
2005, European Journal of Cancer
Nuclear receptors are a family of ligand dependent transcription factors which have important roles in control of growth and differentiation in many cell types. This review will focus on the role of two members of this family (estrogen receptors and PPARγ) in the initiation and progression of lung cancer. These receptors have been studied in other types of cancer, and the differences between findings in lung cancer and other malignancies will be discussed. We will also describe recent studies on the basic mechanisms of action of these receptors and suggest novel therapeutic targets. Specifically, there is emerging evidence that these receptors can induce gene expression through both ligand-dependent and ligand-independent pathways, and distinct families of genes are likely to be regulated depending on the mechanism of nuclear receptor signalling. These data suggest that a greater understanding of the basic biology and mechanisms of these receptors is required to develop specific pharmacological agents as therapeutics for cancer. Specifically, the development of selective agonists for these receptors, such as tamoxifen, may lead to more selective engagement of anti-tumourigenic pathways. In addition, combinatorial therapy using selective nuclear receptor activators in conjunction with the recently developed EGF receptor inhibitors (gefitinib, erlotinib) may sensitise cells which are unresponsive to the effects of EGF receptor inhibitors alone, providing powerful new therapeutic strategies.
Clonality Analysis of Different Histological Components in Combined Small Cell and Non-Small Cell Carcinoma of the Lung
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Combined small cell and non—small cell carcinoma is relatively rare in the lung. Examination of the clonal relationship of different components in this type of tumor may give a clue to the rarity. We retrieved 6 such tumors; all 6 had small cell carcinoma and adenocarcinoma components, and 3 had an additional squamous cell carcinoma component. We examined the point mutations in the p53 gene and allelic loss (ie, the loss of heterozygosity [LOH] pattern) of chromosome 3p in each component. p53 mutations were detected in the small cell carcinoma component of 5 tumors and in the non—small cell carcinoma components of 2 tumors. In 1 case, the squamous cell carcinoma component had a p53 mutation locus identical to that in the small cell carcinoma component, but in the other case, the adenocarcinoma component had a different mutation than that in the small cell carcinoma component. Chromosome 3p LOH loci in the squamous cell carcinoma component were present in the small cell carcinoma component in all 3 cases, but some LOH loci were not identical in the small cell carcinoma and adenocarcinoma components in 3 cases. These results suggest that the small cell and squamous cell carcinoma components of combined small cell lung carcinomas have an intimate clonal relationship. On the other hand, the adenocarcinoma component often may be derived from a separate clone or, more likely, undergo a progressive process separate from the squamous cell—small cell carcinoma beginning in a very early stage, that is, before the appearance of p53 and chromosome 3p abnormalities. This tumorigenesis process may explain the relative rarity of combined small cell and non—small cell carcinoma, which occurs primarily in the peripheral lung, an infrequent site of squamous cell carcinoma.
In vivo expression of p53 and Bcl-2 and their role in programmed cell death in premalignant and malignant lung lesions
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Forty-four specimens of non-malignant and malignant human lung tissue, taken from patients with non-small cell lung cancer (NSCLC), were examined for the expression of wild-type p53, mutant p53, and bcl-2 and the occurrence of programmed cell death (apoptosis). Wild-type p53 expression peaked in peritumoral and metaplastic samples, whereas mutant p53, bcl-2 and apoptosis were first detected in metaplasia and increased with progression to carcinoma. Bcl-2 positive samples had lower levels of apoptosis than bcl-2 negative samples and was independent of wild-type or mutant p53 expression. These results suggest that the over-expression of wild-type p53 may be an early cellular response to an alteration in normal cellular homeostasis. The ensuing increase in apoptosis appears to be relatively independent of mutant or wild-type p53 expression, but does not occur in cells expressing bcl-2.
Induction of cPLA<inf>2</inf> in Lung Epithelial Cells and Non-small Cell Lung Cancer Is Mediated by Sp1 and c-Jun
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Activating mutations in rasgenes are frequently associated with non-small cell lung cancer cells (NSCLC) and contribute to transformed growth in these cells. Expression of oncogenic forms of Ras in these cells is associated with increased expression and activity of cytosolic phospholipase A₂(cPLA₂) and cyclooxygenase-2 (COX-2), leading to constitutively elevated levels of prostaglandin production. Expression of oncogenic Ras is sufficient to induce these enzymes in normal lung epithelial cells. We have previously reported that the JNK and ERK pathways are necessary for induction of cPLA₂ and have defined a minimal region of the cPLA₂ promoter from −58 to −12 that is required for Ha-Ras-mediated induction. To further characterize the cis-regulatory elements within this region involved in this response, site-directed mutagenesis was used to make mutations at various sites. Three cis-regulatory elements were identified: regions −21/−18, −37/−30, and −55/−53. Mutations in any of these elements decreased basal and Ha-Ras-induced cPLA₂ promoter activity in both normal lung epithelial cells, as well as steady state promoter activity in A549 cells, with a mutation in element −21/−18 completely eliminating all promoter activity. Overexpression studies and gel shift assays indicated that Sp1 may serve as a transcription factor functionally regulating promoter activity by directly interacting with two of thecis-regulatory elements, −21/−18 and −37/−30. Expression of Ha-Ras led to induction of c-Jun protein, which showed functional cooperation with Sp1 in driving promoter activity. Additional unidentified transcription factors bound to the regions from −55/−53 and −37/−34.
Induction of cytosolic phospholipase by A<inf>2</inf> oncogenic Ras is mediated through the JNK and ERK pathways in rat epithelial cells
2001, Journal of Biological Chemistry
Mutations in ras genes have been detected with high frequency in nonsmall cell lung cancer cells (NSCLC) and contribute to transformed growth of these cells. It has previously been shown that expression of oncogenic forms of Ras in these cells is associated with elevated expression of cytosolic phospholipase A₂ (cPLA₂) and cyclooxygenase-2 (COX-2), resulting in high constitutive levels of prostaglandin production. To determine whether expression of constitutively active Ras is sufficient to induce expression of these enzymes in nontransformed cells, normal lung epithelial cells were transfected with H-Ras. Stable expression of H-Ras increased expression of cPLA₂ and COX-2 protein. Transient transfection with H-Ras increased promoter activity for both enzymes. H-Ras expression also activated all three families of MAP kinase: ERKs, JNKs, and p38 MAP kinase. Expression of constitutively active Raf did not increase either cPLA₂ or COX-2 promoter activity, but inhibition of the ERK pathway with pharmacological agents or expression of dominant negative ERK partially blocked the H-Ras-mediated induction of cPLA₂ promoter activity. Expression of dominant negative JNK kinases decreased cPLA₂promoter activity in NSCLC cell lines and inhibited H-Ras-mediated induction in normal epithelial cells, whereas expression of constructs encoding constitutively active JNKs increased promoter activity. Inhibition of p38 MAP kinase or NF-κB had no effect on cPLA₂ expression. Truncational analysis revealed that the region of the cPLA₂ promoter from −58 to +12 contained sufficient elements to mediate H-Ras induction. We conclude that expression of oncogenic forms of Ras directly increases cPLA₂ expression in normal epithelial cells through activation of the JNK and ERK pathways.

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Chest

Oncogenes and Antioncogenes in Lung Tumorigenesis

Section snippets

Biological Markers of Lung Cancer

Oncogenes and Tumor Suppressor Genes Involved in Lung Cancer

Conclusions

Cell

Cell

The biology and molecular genetics of lung cancer.

Expression of CD44 in human lung tumors.

Cancer Res

Correlation of intrinsic chemoresistance of non-small cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations.

J Natl Cancer Inst

p53 status and the efficacy of cancer therapy in vivo

Science

Cooperation of c-raf-1 and c-myc protooncogenes in the neoplastic transformation of SV40 T-antigen immortalized human bronchial epithelial cells.

Proc Natl Acad Sci USA

Neoplastic transformation of a human bronchial epithelial cell line by a recombinant retrovirus encoding viral Harvey ras

Mol Carcinog

Biological consequences of overexpression of a transfected c-erbB-2 gene in immortalized human bronchial epithelial cells.

Cancer Res

Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor type Bl.

Proc Natl Acad Sci USA

Mutations of ras genes distinguish a subset of non-small cell lung cancer cell lines from small cell lung cancer cell lines.

Oncogene

ras oncogenes in human cancer: a review.

Cancer Res

p185neu expression in human lung adenocarcinomas predicts shortened survival.

Cancer Res

Mutations in the p53 gene occur in diverse human tumour types.

Nature

Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer.

Oncogene

Abnormalities in structure and expression of the human retinoblastoma gene in SCLC.

Science

A specific chromosome defect associated with human small cell lung cancer: deletion 3p(14-23).

Science

Loss of heterozygosity on chromosomes 3, 13, and 17 in small cell carcinoma and on chromosome 3 in adenocarcinoma of the lung.

Proc Natl Acad Sci USA

myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens.

Cancer Res

bcl-2 protein in non-small cell lung carcinoma.

N Engl J Med

K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung.

N Engl J Med

ras gene mutations in non-small cell lung cancers are associated with shortened survival, irrespective of treatment intent.

Cancer Res

ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis.

Cancer Res