Primary or metastatic pleural tumor cells coexist with mesothelial, endothelial, myeloid lymphoid and other cells. Oncogene signals and/or transcription factor activation in tumor cells determine paracrine gene expression. The balance between vasoactive mediators (e.g., VEGF, TNF, CCL2, OPN, etc) and possible protective molecules (e.g., endostatin) in the pleural space dictates the occurrence of vasoactive signaling with subsequent MPE development. Moreover, this signal cocktail determines further host cell activation and recruitment. In turn, resident and incoming host cells exert a multitude of functions, including direct effects on tumor cells (transcription factor stimulation; rejection, tumor promotion, immunoediting and/or tumor escape) and indirect effects on the pleural vasculature, immune cell populations, and mesothelium to further impact inflammation, angiogenesis, vascular leakage, and/or intrapleural metastasis with establishment of additional pleural-based tumor foci.