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Chromosomal deletion, gene amplification, alternative processing, and autocrine growth factor production in the
J D Minna1, J F Battey, M Birrer
1NCI-Navy Medical Oncology Branch, National Cancer Institute and Naval Hospital, Bethesda, Maryland 20814.
Abstract:
Molecular and cell biologic studies of a large number of lung cancer cell lines of all histologic types have revealed several mechanisms active in the pathogenesis of these cells. Small cell lung cancer (also called "oat cell" lung cancer) has a deletion involving chromosome region 3p(14-23) that is confirmed by DNA restriction fragment length polymorphisms analysis (studies done in collaboration with Dr. Susan Naylor). Several lung cancers of both small cell and non-small cell type (including adeno- and squamous cell lung cancer) express the proto-oncogenes c-, N-, or L-myc, and in some cases more than one of these family members. N-myc appears restricted in its expression to the small cell lung cancer type while c-myc and L-myc can be expressed in both small cell and non-small cell lung cancers. Many lung cancers of all histologic types also express large amounts of p53, which are not correlated with the amount or type of myc gene product expressed. In small cell lung cancer, high levels of myc gene expression are usually associated with gene amplification, and not uncommonly there is rearrangement of some of the amplified copies. In non-small cell lung cancer, expression without amplification or rearrangement of myc genes is seen. In contrast, high level expression of p53 is not associated with gene amplification in any lung cancer type. In addition, to these proto-oncogenes acting at a presumed nuclear locus, there is increased expression of various ras family members and the c-raf-1 proto-oncogene (in collaboration with Dr. Ulf Rapp). Lung cancer cells in tissue culture can grow in medium without serum and few or no other growth factors added. Thus, it appears that lung cancer cells can produce their own growth factors which can act in an "autocrine" fashion. The best characterized example of this is gastrin releasing peptide (GRP, also called bombesin) produced by small cell lung cancer. In at least some small cell lung cancers, interference with GRP action by specific monoclonal antibodies results in inhibition of tumor cell growth in culture and in nude mouse xenografts. Thus, constitutively expressed GRP gene may function as a cellular oncogene under certain circumstances in small cell lung cancer. Based on these observations we are proposing to test monoclonal anti-GRP antibodies in patients.
Insights
Researchers identified key molecular mechanisms in lung cancer pathogenesis, including gene alterations and autocrine growth factor production. Targeting gastrin-releasing peptide (GRP) shows promise for inhibiting small cell lung cancer growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung cancer pathogenesis involves complex molecular and cellular mechanisms.
- Specific genetic alterations and proto-oncogene expressions are observed across various lung cancer types.
Purpose of the Study:
- To investigate the molecular mechanisms underlying lung cancer development.
- To explore the role of proto-oncogenes and autocrine growth factors in lung cancer.
- To evaluate the therapeutic potential of targeting gastrin-releasing peptide (GRP) in small cell lung cancer.
Main Methods:
- Analysis of lung cancer cell lines using DNA restriction fragment length polymorphisms.
- Detection and quantification of proto-oncogene (myc, ras) and p53 expression.
- Assessment of autocrine growth factor production, specifically gastrin-releasing peptide (GRP).
- Inhibition studies using monoclonal anti-GRP antibodies in vitro and in vivo.
Main Results:
- Small cell lung cancer exhibits chromosome 3p deletions and amplified/rearranged myc genes.
- Both small cell and non-small cell lung cancers express various myc family members, ras, and c-raf-1.
- High p53 expression is common but not linked to gene amplification.
- Small cell lung cancer cells produce GRP, and anti-GRP antibodies inhibit tumor growth.
Conclusions:
- Aberrant proto-oncogene expression and autocrine GRP production are critical in lung cancer.
- Targeting GRP with monoclonal antibodies represents a potential therapeutic strategy for small cell lung cancer.