Volk-Draper L, Patel R, Bhattarai N, et al. - In view of their previous reported that myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM) strongly promote lipopolysaccharide-induced inflammatory lymphangiogenesis and that massive numbers of provascular myeloid cells are recruited in breast cancer (BC), researchers examined if, within their recruited population, M-LECPs are particularly programmed to increase tumor lymphatics. In support of this hypothesis, BC patients exhibited high levels of M-LECPs in peripheral blood and tumor tissues. Moreover, patient node status was identified to be strongly correlated with the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins. Furthermore, tumor M-LECPs were identified coexpressing lymphatic-specific, stem/progenitor and M2-type macrophage markers suggesting their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Similar recruitment of mouse M-LECPs to tumors and their integration into preexisting lymphatics were observed using four orthotopic BC models. Finally, it was established that metastatic burden in ipsilateral lymph nodes significantly increase in correlation with adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells. The data thereby support that BC-induced lymphatic progenitors play a causative role in tumor lymphangiogenesis and suggest molecular targets for their inhibition.