M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network. Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data. Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. .

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BackgroundEpidrum® is a recently developed, air operated, loss of resistance (LOR) device for identifying the epidural space. We investigated the usefulness of Epidrum® by comparing it with the conventional LOR technique for identifying the epidural space.MethodsOne hundred eight American Society of Anesthesiologists (ASA) physical status I or II patients between the ages of 17 and 68 years old and who were scheduled for elective surgery under combined spinal-epidural anesthesia were enrolled in this study. The patients were randomized into two groups: one group received epidural anesthesia by the conventional LOR technique (C group) and the second group received epidural anesthesia using Epidrum® (ED group). While performing epidural anesthesia, the values of variables were recorded, including the number of failures, more than 2 attempts, the incidence of dural puncture, the time needed to locate the epidural space, the distance from the skin to the epidural space and ease of performance, and the satisfaction scores.ResultsThe ED group showed a lower failure rate, fewer cases of more than 2 attempts, a lesser time to identify the epidural space, and better ease and satisfaction scores of procedure than the C group, with statistical significance.ConclusionsUsing Epidrum® compared to the conventional LOR technique is an easy, rapid, and reliable method for identifying the epidural space.

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