CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer

Abstract

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.

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

“…The importance of the tumor-associated inflammatory environment is now more and more recognized in many solid tumor contexts and models [154–156]. In particular, a bias in Th1/Th2 cell ratio and/or changes in the circulating cytokine profile are increasingly associated with many solid tumor types, including prostate, oral, ovarian, pancreatic, cervical, colorectal, and breast cancers [157–165].…”

Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression

“…The pro-tumorigenic roles are mediated directly by tumor-associated macrophages, dendritic cells, and endothelial cells along with TLR-mediated cytokine production (Elinav et al, 2013; Hu et al, 2015; Vinnakota et al, 2013). In multiple tumor types, including hepatocellular carcinoma and colorectal, prostate, and bladder cancer, TLRs appear to function more in a pro-tumorigenic role (Cheah et al, 2015; Grimm et al, 2010; Zhao et al, 2015), and the precise outcome of TLR signaling in tumor cells, including CSCs, is an ongoing area of investigation.…”

AMPKα Is Suppressed in Bladder Cancer through Macrophage-Mediated Mechanisms

“…CM from these cells was utilized as a model to test the effects of macrophage secretions on bladder cancer. Differentiated U937 cells upregulate cell surface markers such as CD11b, CD14, and CD68, which are similar to cell surface markers of macrophages in bladder cancer and thus are a relevant model of this disease [33], [34], [35], [36]. Human HTB2 bladder cancer cells, which express both the AMPKα1 and AMPKα2 isoforms, were treated with varying doses of the macrophage CM starting at a dose of 1 part CM to 1 part complete culture media down to 1 part in 31.…”

“…To assess the impact of macrophages on AMPKα, U937 cells which were differentiated with PMA to become macrophage-like cells were utilized because they express similar cell surface markers as the macrophages present in bladder cancer [33], [36], [46]. Treatment of human bladder cell lines with CM from U937 macrophages elicited downregulation of AMPKα1, AMPKα2, and the total AMPKα1/α2 at the protein level but not at the mRNA level.…”