TY - JOUR
T1 - Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer
AU - Volk-Draper, Lisa
AU - Patel, Radhika
AU - Bhattarai, Nihit
AU - Yang, Jie
AU - Wilber, Andrew
AU - DeNardo, David
AU - Ran, Sophia
N1 - Publisher Copyright:
© 2019 American Society for Investigative Pathology
PY - 2019/11
Y1 - 2019/11
N2 - Lymphatic metastasis is a high-impact prognostic factor for mortality of breast cancer (BC) patients, and it directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
AB - Lymphatic metastasis is a high-impact prognostic factor for mortality of breast cancer (BC) patients, and it directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
UR - http://www.scopus.com/inward/record.url?scp=85073439151&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2019.07.006
DO - 10.1016/j.ajpath.2019.07.006
M3 - Article
C2 - 31421071
AN - SCOPUS:85073439151
SN - 0002-9440
VL - 189
SP - 2269
EP - 2292
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 11
ER -