Elucidating the role of lymphatic vessels within the tumor microenvironment of breast cancer

Breast cancer is the most common cancer in women worldwide, with an estimated 1.7 million newly diagnosed cases in 2012. Despite the many clinical manifestations, metastatic disease is the main cause of death, and is responsible for 90% of all breast cancer-related deaths. Aggressive carcinomas of the breast preferentially spread via the lymphogenous route, and often co-opt and actively remodel the lymphatic vasculature in order to invade and metastasize to their draining lymph nodes (LNs) and, ultimately, to distant organs. Indeed, expression of vascular endothelial growth factor (VEGF)-C, the principal lymphangiogenic growth factor, by the tumor or recruited ancillary cells has been shown to correlate both with LN and distant metastasis, and shorter overall survival (OS), and LN status represents an important prognostic factor for patients diagnosed with breast cancer. Although traditionally considered as passive conduits that solely mediate tumor cell escape, more recent research aimed at discerning the interactions between the developing tumor and its associated lymphatic vessels has revealed that the lymphatic vasculature actively promotes lymphogenous metastasis of invasive tumor cells. Likewise, collaborative interactions between tumor cells and a multitude of other tissue-resident and recruited ancillary cells, which together constitute the tumor microenvironment, not only coercively contribute to tumor growth, progression and metastasis, but also suggest that interactions among primed stromal cells themselves may be important in the process of metastatic dissemination as well. Notably, expansion of tumor-associated lymphatic vessels in the tumor periphery leads to increased lymphatic drainage from the tumor to the tumor-draining LN, and interstitial flow-induced mechanical changes may alter tensional homeostasis within the tumor through stimulation of local fibroblasts that remodel and stiffen the extracellular matrix (ECM). Furthermore, VEGF-C-induced remodeling of the tumor-associated lymphatic vasculature has been shown to directly suppress the anti-tumor immune response, thereby promoting tolerance to the nascent tumor. Thus, to explore whether tumor-associated lymphatic vessels promote tumor metastasis not only via interactions with the incipient tumor, but also through cross-talk with the surrounding stromal cells, the different components of the tumor microenvironment, specifically tensional homeostasis and anti-tumor immunity, were evaluated upon modulation of lymphatic vessel growth in various experimental models of breast cancer. Accordingly, inhibition of VEGFR-3-mediated signaling upon administration of an antagonistic antibody in a genetically engineered preclinical mouse model specifically reduced the number of lymphatic endothelial cells (LECs) in the tumor, whereas conversely, orthotopic inoculation of a stable murine breast cancer cell line with enhanced expression of VEGF-C induced an expansion of the lymphatic endothel