5 research outputs found
Post-World War II Greek emigration causes and effects
Digitized by Kansas Correctional Industrie
Osteopontin drives KRAS-mutant lung adenocarcinoma
Increased expression of osteopontin (SPP1) is associated with aggressive human lung adenocarcinoma, but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced lung adenocarcinoma. We combined mouse models of tobacco carcinogen-induced lung adenocarcinoma, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant KrasG12C in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRASG12D mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human lung adenocarcinoma and portended poor survival. In response to two different smoke carcinogens, Spp1-deficient mice developed fewer and smaller lung adenocarcinoma with decreased cellular survival and angiogenesis. Both lung epithelial- and macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS-mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRASG12D-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target
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