Many cancers, including breast, colon, prostate, and skin cancers, spread and metastasize preferentially through the lymphatic system (lymphogenous metastasis). Despite the prevalence of lymphogenous metastasis and its dire consequences for patient survival, little is known about how tumor cells locate and migrate to lymphatic vessels, enter into the vessels, and then travel to the lymph nodes. Using a novel toolkit consisting of models for the tumor microenvironment, lymphatic vessels, and the lymph nodes, we are asking questions about the mechanisms and molecules involved in each step of this process. To examine the tumor microenvironment, we have developed a number of in vitro models that incorporate interstitial flow, a 3D matrix, various cell types. We have employed a 3D transwell assay to demonstrate that breast cancer cells migrate in the direction of interstitial flow, and that this migration is dependent on the chemokine receptor CCR7. Once tumor cells reach the lymphatics, they must enter the vessel and then travel downstream to the lymph nodes. Using a 3D model of the tissue space that includes interstitial flow and a draining lymphatic vessel mimic, we answered questions such as how tumor cells intravasate into lymphatics, and specifically what adhesion molecules are involved in this process. To model the behavior of tumor cells once they are inside the lymphatic vessel, tumor cells are flowed over a monolayer of LECs to quantify behaviors such as rolling, attachment, and adhesion. Taken together, this continuum of models of the tumor-lymphatic interface addresses many aspects of lymphogenous metastasis: the tumor microenvironment (and the role played by other cell types), homing to lymphatic vessels, and subsequent intravasation and trafficking to lymph nodes. Throughout, we emphasize the importance of interstitial fluid flow as a biophysical phenomenon that has a profound effect on cancer cell migration, invasion, and metastasis.
- “An in vitro model of the tumor-lymphatic microenvironment with simultaneous transendothelial and luminal flows reveals mechanisms of flow enhanced invasion”, Pisano M, Triacca V, Barbee KA, Swartz MA. Integrative Biology, 2015.
- “Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism”, JM Munson, RV Bellamkonda, MA Swartz. Cancer Research, 2013.
- “Tumor cell invasion is promoted by interstitial flow-induced matrix priming by stromal fibroblasts”, Shieh AC, Rozansky HA, Hinz B, Swartz MA. Cancer Research, 2011.
- “Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype”, Issa A, Le TX, Shoushtari AN, Shields JD, Swartz MA. Cancer Research, 2009.
- “Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling”, Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Cancer Cell, 2007