3 research outputs found
Mutant KRAS promotes malignant pleural effusion formation
Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition
Mast cells mediate malignant pleural effusion formation
Mast cells (MCs) have been identified in various tumors; however, the
role of these cells in tumorigenesis remains controversial. Here, we
quantified MCs in human and murine malignant pleural effusions (MPEs)
and evaluated the fate and function of these cells in MPE development.
Evaluation of murine MPE-competent lung and colon adenocarcinomas
revealed that these tumors actively attract and subsequently degranulate
MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were
required for effusion development, as MPEs did not form in mice lacking
MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE
formation. Once homed to the pleural space, MCs released tryptase AB1
and IL-1 beta, which in turn induced pleural vasculature leakiness and
triggered NF-kappa B activation in pleural tumor cells, thereby
fostering pleural fluid accumulation and tumor growth. Evaluation of
human effusions revealed that MCs are elevated in MPEs compared with
benign effusions. Moreover, MC abundance correlated with MPE formation
in a human cancer cell-induced effusion model. Treatment of mice with
the c-KIT inhibitor imatinib mesylate limited effusion precipitation by
mouse and human adenbcarcinoma cells. Together, the results of this
study indicate that MCs are required for MPE formation and suggest that
MC-dependent effusion formation is therapeutically addressable