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Bioactive lipids in tobacco related lung cancers

Institution: University of California, San Diego
Investigator(s): Jerold Chun, M.D., Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6IT-0375 Award: $74,496
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
A major cause of morbidity and mortality related to tobacco smoking is lung cancer. Understanding how the growth and metastatic invasion of cancer cells is controlled will allow the rationale development of therapies for this important tobacco related disease. One form of lung cancer, the small cell lung cancers (SCLCs), can be stimulated to grow more aggressively by natural chemicals that are present within the blood. One such factor is a kind of fat molecule referred to as a phospholipid. A particularly important phospholipid is lysophosphatidic acid (LPA), which has many of the same properties as growth factors. For example, LPA causes some cells to proliferate, and produces changes in cell shape that are mediated by structural proteins present within cells. LPA also stimulates specific types of molecules within a cell that lead to the expression of previously inactive genes.

In SCLC models, LPA promotes cell invasion and proliferation. The mechanisms through which LPA operates in these lung cancers, however, have been difficult to address because of debate about whether the primary action of LPA was through a receptor or rather was due to nonreceptor, cell membrane dissruptions; no cloned receptor for LPA has been available to answer the question.

Our laboratory has recently published the first cloned receptor for LPA. In the current project, we will examine the role of the LPA receptor in lung cancers particularly SCLCs using molecular genetic and pharmacological approaches. We will test the hypothesis that LPA, through receptor mediated mechanisms, controls the proliferation and invasiveness of SCLCs, and influences the proliferative response of other forms of lung cancers as well. The hypothesis will be tested by 3 specific aims. Aim 1 will determine the amount of the LPA receptor in lung cancers by screening a range of different lung cancers. Aim 2 will determine the effects of different amounts of LPA receptors. Aim 3 will examine the signal transduction pathways utilized by the responsive cancer cells respond to LPA. From these analyses, the role of receptormediated action of LPA on lung cancer behaviors will be determined. Evidence for LPA actions on the biology of these cancers will suggest new strategies in treating this tobacco-related disease.

Final Report
This proposal has as its major goal, understanding the influence of small, extracellular fats (lipids) on the biology of lung cancer cells. It will test the hypothesis that one such lipid, called "lysophosphatidic acid" or LPA, through interaction with a cell surface receptor, controls the proliferation and/or invasiveness of lung cancers, particularly small cell lung cancers (SCLCs) and non-small cell lung cancers (NSLCs). The approach to this problem involves three specific aims: 1) determine the prevalence of the LPA receptor m lung cancers by screening different lung cancers/related cell lines by northern and western blot analyses, 2) determine the proliferative or invasive effects of LPA receptor overdxpression and underexpression on lung tissue cell lines, and 3) determine the germane signal transduction pathways utilized by those cells expressing the LPA receptor.

The proposal was based on the identification of the first, and at the time only, LPA receptor referred to as "vzg-1." However, over the past year, we realized that it was but one of several related receptors that could also mediate the effects of this and related lipid molecules. Because of the importance of a defined set of receptors, we have spent most of our effort in isolating DNA clones of the new, putative receptors, and have spent additional effort in determining their functional identity, to be certain that they were indeed LPA receptors. The need to pursue this line of research has slowed our initial plans to screen lung cancer cells, but it made far more sense to have as complete a "library" of receptors as possible to understand fully which receptors were actually mediating the reported effects of LPA and perhaps related lipids.

Based on this analysis, we have identified 5-6 new receptors from murine cells (mice provide a strong biological system for our studies). These receptors fall into two major groups based on their similarity to one another, and based on their DNA coding structures (their "genomic" structures). We have found that they all interact with structurally related molecules that are "lysophospholipids" and thus have been referred to as "lysophospholipid receptors." Lysophospholipid receptor A (LP,,,) members interact with LPA, whereas LPB members interact with a similar molecule referred to as sphingosine-1-phosphate or SlP. Having this information in hand will soon allow us to categorize lung cancers based on their expression of these receptor genes, and allow us to design experiments that can more accurately determine the interaction of lung cancer cells with this novel class of lipid signals.
Publications

A growing family of receptor genes for lysophosphatidic acid (LPA) and other lysophospholipids (LPs)
Periodical: Cell Biochemistry and Biophysics Index Medicus:
Authors: Chun J, Contos JJA, Munroe D ART
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