Progression and Metastasis of Lung Cancer A Study of Predominant Cellular Interactions in Tumor Microenvironment

Abstract

The heterotypic view of cancer envisions solid tumors as ecosystems consisting of abnormal epithelial tumor cells and a plethora of cell types collectively referred to as stromal cells. In these ecosystems, innate immune cells are highly represented and most abundant among these are macrophages. Macrophages commonly designated as Tumor associated macrophages (TAMs) in the tumor microenvironment,originate from circulating pool of monocytes and play a critical role in orchestrating and promoting tumor growth. The acquisition of tumorigenic properties by TAMs relies upon a complex interplay between them and tumor cells. In this study, we demonstrated through co-culture experiments that such properties of TAMs are shaped up by the tumor-derived secretory signals which favor their tumor promoting phenotypes. Co-culture of model human monocytes (THP-1) with model human lung carcinoma cells (A549) enabled THP-1 cells to secrete tumor-promoting cytokines and therefore enhanced proliferation, migration and invasiveness of A549 cells. We demonstrated that A549 cells consistently secrete EDA-containing Fibronectin that mediates the pro-inflammatory response from THP-1 monocytes in a paracrine manner. Ablation of such responses by the treatment of THP-1 cells with TLR-4 blocking antibody implicated Fibronectin-TLR4 axis in tumor-associated inflammation and suggests a paradigm wherein lung carcinoma cell derived EDA-containing Fibronectin drives a pro-inflammatory and pro-metastatic tumor microenvironment. Intriguingly, it was also observed that the EDA-containing Fibronectin from A549 cells promotes their migration, invasion and anchorage independent growth in an autocrine fashion. Finally, we showed that the EDA-containing Fibronectin imparts metastatic capacity to A549 cells through the activation of epithelial mesenchymal transition program. Collectively this study identifies a mechanism of communication between lung carcinoma cells and monocytes and reveals a novel oncogenic role of lung cancer derived EDA-containing ...