"Inflammation and Cancer:  How are they linked?"

Cheng Dong, PhD
Distinguished Professor of Bioengineering
Pennsylvania State University 

Attachment of tumor cells to the endothelium (EC) under flow conditions is critical for the migration of tumor cells out of the vascular system to establish metastases. The interactions between cancer cells and the host immune system are of particular interest to our group. Innate immune system processes can potentially promote tumor progression through inflammation dependant mechanisms. Human neutrophils (PMNs), which comprise 50-70% of circulating leukocytes, are being studied to better understand how the host immune system affects cancer cell adhesion and subsequent migration and metastasis.

Melanoma cell interaction with the EC is distinct from PMN-EC adhesion in the circulation. We found PMN increased melanoma cell extravasation, which involves initial PMN tethering on the EC and subsequent PMN capture of melanoma cells and their delivery to close proximity to the EC. LFA-1 (CD11a/CD18 integrin) influenced the capture phase of PMN binding to both melanoma cells and the endothelium, while Mac-1 (CD11b/CD18 integrin) affected prolonged PMN-melanoma aggregation. Blocking Eselectin or ICAM-1 (intercellular adhesion molecule) on the endothelium or ICAM-1 on the melanoma surface reduced PMN-facilitated melanoma extravasation. Results indicate a novel finding that PMN-facilitated melanoma cell arrest on the EC is modulated by the hydrodynamic shear rate that affects the on-rate (kon) adhesion kinetic constant in PMN-melanoma cell aggregations; rather than by the flow shear stress which is the force exerted on formed adhesion bonds. In addition, melanoma-induced inflammatory cytokine IL-8 contributes to PMN tethering and subsequent melanoma arrest on the EC via the PMN-melanoma cell binding. Functional blocking of the IL-8 receptors CXCR1 and CXCR2 on PMNs, or neutralizing soluble IL-8 in cell suspensions, significantly decreased the level of Mac-1 up-regulation on PMNs while in communicating with melanoma cells and reduced melanoma extravasation. We also found that activation of nuclear factor of B (NF-B) in PMNs is responsible for endogenous IL-8 production in response to melanoma microenvironment. These results provide new evidence for the complex role of hemodynamic forces, secreted chemokines, and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the endothelium in the microcirculation, which are significant in fostering new approaches to cancer treatment through anti-inflammatory therapeutics. (This work was supported by NIH CA-125707 and NSF CBET 0729091.)