CCR7 is implicated in lymph node metastasis of cancer, but its role is obscure. We report a mechanism explaining how interstitial flow caused by lymphatic drainage directs tumor cell migration by autocrine CCR7 signaling. Under static conditions, lymphatic endothelium induced CCR7-dependent chemotaxis of tumor cells through 3D matrices. However, interstitial flow induced strong increases in tumor cell migration that were also CCR7 dependent, but lymphatic independent. This autologous chemotaxis correlated with metastatic potential in four cell lines and was verified by visualizing directional polarization of cells in the flow direction. Computational modeling revealed that transcellular gradients of CCR7 ligand were created under flow to drive this response. This illustrates how tumor cells may be guided to lymphatics during metastasis.

Interstitial flow plays important roles in the morphogenesis, function, and pathogenesis of tissues. To investigate these roles and exploit them for tissue engineering or to overcome barriers to drug delivery, a comprehensive consideration of the interstitial space and how it controls and affects such processes is critical. Here we attempt to review the many physical and mathematical correlations that describe fluid and mass transport in the tissue interstitium; the factors that control and affect them; and the importance of interstitial transport on cell biology, tissue morphogenesis, and tissue engineering. Finally, we end with some discussion of interstitial transport issues in drug delivery, cell mechanobiology, and cell homing toward draining lymphatics.

BackgroundBarriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research.MethodsWe conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings.ResultsWe identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval [CI] = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% [95% CI = 13.8% to 18.2%]) vs community (7.0% [95% CI = 5.1% to 9.1%]) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment.ConclusionsThese findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.