RT Journal Article
SR Electronic
T1 A requirement for kras signaling in malignant pleural effusion
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1513
VO 42
IS Suppl 57
A1 Antonia Marazioti
A1 Ardiana Moustaki
A1 Magda Spella
A1 Anastasios Giannou
A1 Marianthi Iliopoulou
A1 Dimitris Kardamakis
A1 Georgios Stathopoulos
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/1513.abstract
AB Malignant pleural effusion (MPE) is usually caused by metastatic adenocarcinomas. Although these tumors frequently harbor Kras mutations (ΔKras), a relationship between mutant Kras and MPE formation has not been established. For this, we genotyped murine tumors for ΔKras and related mutations and assessed their potential for MPE formation. LLC lung adenocarcinoma, MC38 colon adenocarcinoma, and AE17 pleural mesothelioma were capable of MPE formation and all harbored ΔKras. In contrast, B16F10 melanoma and PANO2 pancreatic adenocarcinoma did not cause MPE and had wtKras. The contrasting pleural phenotypes of ΔKras versus wtKras tumors were not associated with different rates of tumor growth, but with an enhanced propensity of ΔKras tumors for precipitation of inflammation, angiogenesis, and vascular leakage. shRNA-mediated knock-down of Kras in ΔKras tumors severely hampered their ability for MPE formation, despite sustained in vivo growth. Kras silencing led to meaningful reductions in MPE-associated inflammation, angiogenesis, and vascular hyperpermeability, changes accompanied by significant inhibition of pro-inflammatory mediator expression and myeloid cell recruitment. Kras overexpression in B16F10 cells led to minor induction of pleural fluid accumulation, but failed to fully restore the MPE-competent phenotype of ΔKras tumors, suggesting possible cooperation of Kras with additional pathways during MPE development. In conclusion, we demonstrate a requirement for tumor cell-originated Kras signals in the pathogenesis of MPE. Pending the identification of additional ΔKras co-operators, Kras signaling may present an important therapeutic target against MPE.These studies were supported by the ERC.