CD40 pathway activation reveals dual function for macrophages in human endometrial cancer cell survival and invasion.

Reproductive malignancies are a major cause of cancer death in women worldwide. CD40 is a TNF receptor family member, which upon activation may mediate tumor regression. However, despite the great potential of CD40 agonists, their use as a therapeutic option for reproductive cancers has never been investigated. Because CD40 ligation is a potent pathway of macrophage activation, an in vitro model of pro-inflammatory type-1 (Mϕ-1) and anti-inflammatory type-2 (Mϕ-2) macrophages was developed to determine whether and how macrophage CD40 pathway activation might influence endometrial tumor cell behavior. Analysis of tumor growth kinetic in the endometrial cancer xenograft model indicates that, when injected once into the growing tumors, CD40-activated Mϕ-1 greatly reduced, while CD40-activated Mϕ-2 increased tumor size when compared to control isotype-activated Mϕ-1 and Mϕ-2, respectively. In vitro assays indicated that CD40-activated Mϕ-2 increased cell viability but failed to promote cell invasion. CD40-activated Mϕ-1, in contrast, decreased cell survival but greatly increased cell invasion in tumor cells less susceptible to cell death by apoptosis; they also induced the expression of some pro-inflammatory genes, such as IL-6, LIF, and TNF-α, known to be involved in tumor promotion and metastasis. The presence of IFN-γ is minimally required for CD40-activated Mϕ-1 to promote tumor cell invasion, a process that is mediated in part through the activation of the PI3K/Akt2 signaling pathway in tumor cells. From these results, we speculate that some functions of CD40 in tumor-associated Mϕs might limit the therapeutic development of CD40 agonists in endometrial cancer malignancies.

Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells.

Findings from numerous studies suggest that inflammation is likely to have an important role in bladder carcinogenesis and cancer disease progression. While macrophages (Mϕs) constitute a major inflammatory component of the stroma of human bladder carcinoma, the regulatory role of such inflammatory leukocytes in tumor cell survival and invasion remains elusive. Human urothelial bladder cancer (UBC) T24 cells and monocyte-derived macrophages were used to study the relative contribution of pro-inflammatory type-1 (Mϕ-1) and anti-inflammatory type-2 (Mϕ-2) macrophages in the regulation of UBC cell behaviour. Cell-to-cell studies indicated that the number of viable cells were considerable higher in T24 cell/Mϕ-2 cocultures but lower in T24 cell/Mϕ-1 cocultures when compared to cultures of T24 cells alone. Mϕ-1-derived factors inhibit T24 cell growth but fail to induce caspase-3-mediated apoptosis. Mϕ-2-derived factors have the ability to suppress the inhibitory effect of Mϕ-1-derived factors on T24 cell growth. Exogenous interleukin (IL)-10 reverse Mϕ-1-mediated arrest growth in T24 cell/Mϕ-1 cell cocultures. Further analyses showed that Mϕ-1-derived factors induced tumor necrosis factor (TNF)-α gene expression, promoted cellular invasiveness and increased phosphoinositide 3-kinase (PI 3-K)/Akt signaling pathway activity in T24 cells. Inhibition of PI 3-K activation in T24 cells or blockade of TNFα receptor in T24 cell/Mϕ-1 cell cocultures decreased cellular invasiveness but did not affect T24 cell viability. Based on these observations, we propose that similar functional interactions between UBC cells and infiltrating macrophages can take place in vivo and influence tumor cell survival and invasion during bladder cancer progression.