Lung cancer is the leading cause of cancer deaths, largely due to the presence of metastasis at the time of diagnosis. During the past 25 years, studies in epithelial cancers have defined genetic changes in the tumor cells themselves. However, cancer progression and metastasis requires complex interactions between tumor cells and the surrounding stroma. Our laboratory has studied the role of cytosolic phospholipase A2-? (cPLA2) in the development of lung cancer. cPLA2 represents the rate-limiting step in production of a family of eicosanoids with diverse affects in cancer progression. We have demonstrated that cPLA2 knockout (KO) mice are protected against chemically-induced lung tumorigenesis. However, these studies do not discriminate between the action of cPLA2 in the tumor cells versus the surrounding tumor microenvironment (TME). To address this question, we developed a model in which mouse tumor cells are directly injected into the lungs of syngeneic, immune-competent mice. These cells form well-defined primary tumors which metastasize to other lobes of the lungs, the mediastinal lymph nodes and to distant organs including the liver and brain. Importantly, when identical cells are injected into cPLA2-KO mice, primary tumor growth is not significantly altered, but there is a profound inhibition of metastasis. Tumors growing in cPLA2-KO mice exhibit alterations in the pattern of macrophages surrounding the tumor, supporting a role for cPLA2 in macrophage recruitment/function. Transplantation of cPLA2 KO bone marrow into wild-type mice was sufficient to inhibit tumor metastasis and promote survival. These data demonstrate that cPLA2 has distinct effects both in tumor cells and cells of the TME. We therefore hypothesize these effects are mediated through distinct eicosanoids which are produced in a cell-specific and time dependent fashion. While previous work by many laboratories including our own has focused on the effects of specific eicosanoids, there has not been a systematic examination of the spectrum of products produced through cPLA2 and the role these molecules play in cancer progression. The advent of mass spectrometric approaches allows us to define these molecules in an unbiased way, and determine their biological effects. This project will use this approach to define the role of cPLA2 and eicosanoids in distinct cell types using both in vivo and in vitro approaches.
Four Specific Aims are proposed.
Aim 1 will define the eicosanoid spectrum during tumor progression in tumors, surrounding stroma, uninvolved lung and distant organs. The effects of deleting cPLA2 in specific compartments will be correlated with changes in tumor progression and alterations in the TME.
Aim 2 will use in vitro studies to examine the role of cPLA2 in cancer cells and macrophages, as well as in cross-talk between these cells. Mechanistic studies will define the role of specific eicosanoids and their downstream effectors.
Aim 3 will use mice deficient in production of PGE2 or LTC4 to define the role of these products in tumor progression. Finally Aim 4 will examine eicosanoid profiles in human lung cancers and correlate this with clinical data and mutational status.
Progress in treating lung cancer has been difficult because metastasis has frequently occurred at the time of diagnosis. Increased levels of eicosanoids have been associated with many types of cancer, but a systemic identification of these molecules using lipidomic approaches has not been performed. This project will define the spectrum of eicosanoids produced in lung cancer progression and metastasis using both in vivo models and in vitro systems and determine their molecular mechanism of action. These experiments will allow a more rational approach in using pharmacological agents targeting these pathways in treatment of lung cancer.
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