Abstract A49: Tumor-associated interstitial flow promotes macrophage migration and pro-metastatic M2 phenotype in 3D ECM

The growth of solid tumor is often accompanied by an increase in the flow of interstitial fluid (interstitial flow) from the center of the tumor to the surrounding stroma. Recent studies have shown that elevated interstitial flow can influence the migration of cancer cells and fibroblasts. Despite these findings, the effects of interstitial flow on macrophages, one of the key metastasis-promoting tumor-associated stromal cell types, have not been explored. We used microfluidic and transwell flow assays to investigate how high level of interstitial flow (~3 μm/s) often observed in tumor affect macrophage migration and protein expression. We found that interstitial flow not only enhanced macrophage migration speed, but also directed macrophages to migrate against the flow in 3D extracellular matrix. Moreover, we discovered that interstitial flow activated Akt and FAK, two kinases that are crucial for cell migration. Interestingly, interstitial flow also up-regulated macrophage expression of M2 markers Arg I and TGFβ through the activation of JAK1-STAT3/6 pathway. Finally, macrophages treated with interstitial flow were shown to have enhanced abilities to promote cancer cell migration and protrusion formation. Taken together, these results suggest that interstitial flow can promote metastasis through its effects on macrophages. Specifically, since macrophages migrate against the flow, interstitial flow, which emanates from the tumor, can act as a mechanical stimulus to recruit macrophages into tumor tissues. Moreover, interstitial flow can activate macrophages and polarize them toward pro-metastatic M2 phenotype to further promote tumor metastasis and immunosuppression. Citation Format: Ran Li, Hao Xing, Tara A. Lee, Hesham Azizgolshani, Roger D. Kamm. Tumor-associated interstitial flow promotes macrophage migration and pro-metastatic M2 phenotype in 3D ECM. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A49.