| Secreted mediators |
| Osteopontin (OPN; secreted phosphoprotein 1) |
Elaborated by tumor (adenocarcinoma, mesothelioma) and host (macrophages) cells. Short intracellular isoform promotes tumor cell survival. Long secreted isoform signals to tumor, myeloid, and endothelial cells. Different roles for tumor and host cell-secreted cytokine. Recruitment of macrophages, provocation of vascular permeability, induction of new vessel formation, inhibition of apoptosis. |
18, 19
|
| C-C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein-1) |
Elaborated by tumor and host cells. Signals to tumor, myeloid, and endothelial cells. Role of host-originated chemokine not known. Recruitment of macrophages and mast cells, provocation of vascular permeability, induction of new vessel formation. |
17 |
| Vascular endothelial growth factor (VEGF) |
Secreted by tumor and host cells. Signals to endothelium and VEGFR-expressing macropahges. Provokes vascular permeability, induces new vessel formation, and facilitates leukocyte transendothelial migration. |
10–12
|
| Tumor necrosis factor (TNF) |
Low level production by tumor cells; high levels secreted by activated macrophages. Provocation of vascular permeability, induction of new vessel formation, inhibition of tumor cell apoptosis via activation of nuclear factor-κB. |
16 |
| Angiopoietins 1 and 2 |
Secreted by tumor and (mainly) host endothelial cells. Induction of new vessel formation, regulation of vascular assembly. Recruitment of neutrophils and macrophages. |
20, 38
|
| Interleukin-5 |
Produced exclusively by host myeloid and lymphoid cells. Recruitment/activation of eosinophils and tumor-promoting myeloid suppressor cells. |
15 |
| Interleukin-6 |
Expressed by both tumor and host cells. Activates signal transducer and activator of transcription 3 in tumor cells. |
23 |
| Tumor cell transcription factors |
| Signal transducer and activator of transcription 3 |
Activated by interleukin-6, leads to enhanced vascular endothelial growth factor expression by tumor cells. |
23 |
| Nuclear factor-κB |
Activated by tumor necrosis factor, promotes tumor cell survival, vascular endothelial growth factor and C-C motif chemokine ligand 2 expression. |
14, 39
|
| Tumor cell genetic alterations |
| Epidermal growth factor receptor |
Mutations found more frequently in pleural metastasis compared with primary lung cancer site. Cases of mutation discordance between pleural metastasis and matched primary lung cancer site identified. Common mutation in lung adenocarcinoma, the most common cause of MPE. EGFR signaling promotes tumor angiogenesis and vascular leakage. |
24,25,40
|
| KRAS |
Cases of mutation discordance between pleural metastasis and matched primary lung cancer site. Common mutation in lung adenocarcinoma, the most common cause of MPE. |
25 |
| Host cell populations |
| Neutrophils |
Recruited to mesothelioma and polarized to N2 pro-tumorigenic phenotype by transforming growth factor-β. N2 promote mesothelioma growth, but impact on MPE formation uncertain. |
29 |
| Mononuclear cells/macrophages |
Recruited to pleural space by CCL2. Role in MPE formation uncertain. |
17 |
| Myeloid-derived suppressor cells |
Immature myeloid cells expressing both monocyte and granulocyte markers. Known pro-tumor function via suppression of effector T cells. Role in MPE uncertain. |
15 |
| Eosinophils |
Low numbers present in most human and mouse MPEs examined. Reduced numbers were found in interleukin-5-deficient mice. Role in MPE formation uncertain. |
15 |
| Regulatory T cells |
Recruited to pleural space by CCL22. Role in MPE uncertain. |
32–33
|
| Mesothelial cells |
Produce VEGF and express its receptor. Role in MPE formation uncertain. |
27 |
