During the past 25 years, studies in epithelial cancers have defined genetic changes in the tumor cells themselves. However, it is clear that cancer progression and metastasis requires complex interactions between tumor cells and the surrounding stromal. Our work has studied the role of cytosolic phospholipase A2 (cPLA2) in the development of lung cancer, focusing on tumor cells themselves. Activation of cPLA2 represents the rare limiting step in prostaglandins(PG) production. Constitutive increases in PG production are associated with many cancers, including non-small cell lung cancer (NSCLC). We have shown that NSCLC cell lines expressing oncogenic K-Ras have elevated levels of PGE2 production, mediated through induction of cPLA2 and COX-2. Blocking this pathway inhibits transformed growth in vitro and in xeno graft models, supporting a role for cPLA2 in lung cancer progression. However, less is known regarding the role of cPLA2 in the tumor microenvironment. During the past funding period, we showed that cPLA2 knockout (KO) mice are protected against chemicallyinduced lung tumorigenesis. However, these studies do not discriminate between the action of cPLA2 in the tumor cells versus the surrounding stromal. To address the function of cPLA2 in the tumor microenvironment, we have developed a model in which mouse tumor cells are directly injected into the lungs of syngeneic, immune competent mice. Using bioluminescence imaging we have shown that these cells form well-defined primary tumors which metastasize to other lobes of the lungs and into the mediastinal lymph nodes. When identical cells are injected into cPLA2 KO mice, while primary tumor growth is not significantly altered, there is a profound inhibition of metastasis. Tumors growing in cPLA2 KO mice exhibited alterations in the pattern of macrophages surrounding the tumor, supporting a role for cPLA2 in macrophage recruitment/function. Transplanting cPLA2 KO bone marrow into wild-type mice was sufficient to inhibit tumor metastasis and promote survival. Based on these results, we hypothesize that cPLA2 is required for mobilization and/or function of tumor associated macrophages which play a critical role in lung cancer progression and metastasis. This project will investigate the role of cPLA2 in both tumor cells and stromal, and define molecular events mediated by cPLA2 in both compartments.
Two Specific Aims are proposed.
Aim 1 will assess the contribution of cPLA2 in stromal cells using murine lung cancer cells injected into either WT or cPLA2 KO mice. Changes in stromal cells will be defined and in vitro co-cultures will examine cross-talk between cancer cells and macrophages.
Aim 2 will use genetic mice to define the downstream effectors of cPLA2 in the tumor microenvironment. These studies will provide a better understanding of tumor-stromal interactions critical for metastasis and define therapeutic targets to block progression of lung cancer.
Progress in treating lung cancer has been difficult because metastasis has frequently occurred at the time of diagnosis. Our published data indicate that cytosolic phospholipase A2 is critical for interactions between tumor cells and macrophages, which in turn mediate lung cancer progression and metastasis. This project will examine mechanisms mediating interactions between tumor cells and the tumor microenvironment and will define new therapeutic targets to specifically target metastasis.
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