期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：4725-4730
DOI：10.1073/pnas.1424795112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceOur study defines the crucial role of CD14-high bladder cancer (BC) cells in orchestrating multiple hallmarks of cancer in the early stages of BC. Inflammatory factors produced by this subpopulation of tumor cells activate angiogenesis to support establishment and maintenance of an immune-suppressive, inflammatory tumor microenvironment. Additionally, this subpopulation is able to drive tumor growth by producing factors that drive autocrine and paracrine proliferative stimulation. Here we show that a tumor-cell subpopulation establishes a tumor microenvironment orchestrating tumor-promoting inflammation and tumor-cell proliferation. Collectively, this study highlights the need to explore the broader role of CD14-expressing neoplastic cells in other solid tumors. It is noteworthy that CD14 expression is critical for IL6 secretion by these cells. Therefore, therapeutic targeting of CD14 might represent a strategy for treating cancer. Nonresolving chronic inflammation at the neoplastic site is consistently associated with promoting tumor progression and poor patient outcomes. However, many aspects behind the mechanisms that establish this tumor-promoting inflammatory microenvironment remain undefined. Using bladder cancer (BC) as a model, we found that CD14-high cancer cells express higher levels of numerous inflammation mediators and form larger tumors compared with CD14-low cells. CD14 antigen is a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein and has been shown to be critically important in the signaling pathways of Toll-like receptor (TLR). CD14 expression in this BC subpopulation of cancer cells is required for increased cytokine production and increased tumor growth. Furthermore, tumors formed by CD14-high cells are more highly vascularized with higher myeloid cell infiltration. Inflammatory factors produced by CD14-high BC cells recruit and polarize monocytes and macrophages to acquire immune-suppressive characteristics. In contrast, CD14-low BC cells have a higher baseline cell division rate than CD14-high cells. Importantly, CD14-high cells produce factors that further increase the proliferation of CD14-low cells. Collectively, we demonstrate that CD14-high BC cells may orchestrate tumor-promoting inflammation and drive tumor cell proliferation to promote tumor growth.
关键词：bladder cancer ; CD14 ; inflammation ; microenvironment
