Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis

Abstract

Endometriosis affects 10-15% of women and is associated with pelvic pain and infertility. Angiogenesis plays an essential role in its pathogenesis. Dendritic cells (DCs) were recently implicated in supporting tumor angiogenesis. As both tumors and endometriosis lesions depend on angiogenesis, we investigated the possibility that DCs may also play a role in endometriosis. We induced endometriosis in 8-wk-old female C57BL/6 mice by implantation of autologous endometrium into the peritoneal cavity. We observed an abundance of CD11c(+) DCs infiltrating sites of angiogenesis in endometriosis lesions. We noticed a similar pattern of infiltrating DCs at sites of angiogenesis in the peritoneal Lewis lung carcinoma tumor model. These DCs were immature (major histocompatability complex class II(low)) and expressed vascular endothelial growth factor receptor 2. Peritoneal implanted bone marrow-derived DCs (BMDCs) incorporated into both endometriosis lesions and into B16 melanoma tumors and enhanced their growth at 8 days compared with controls (5.1+/-2.5 vs. 1.5+/-0.5 mm(2), n=4 and 4, P<0.0001 for endometriosis; 67.6+/-15.1 vs. 22.7+/-14.6 mm(2), n=5 and 7, P=0.0004 for mouse melanoma). Finally, immature BMDCs but not mature BMDCs enhanced microvascular endothelial cell migration in vitro (219+/-51 vs. 93+/-32 cells, P=0.02). Based on these findings, we suggest a novel role for DCs in supporting angiogenesis and promoting lesion growth both in endometriosis and in tumors.

Macrophages Are Alternatively Activated in Patients with Endometriosis and Required for Growth and Vascularization of Lesions in a Mouse Model of Disease

“…In support to this model, the peritoneal fluid of patients with endometriosis interferes with in vitro differentiation of precursors challenged with recombinant cytokines, favoring their differentiation toward macrophages 9 and immature dendritic cells injected into endometriotic mice intraperitoneally actively migrate and infiltrate ectopic endometrial lesions, where they contribute to lesions further development. 49 In conclusion, our findings indicate that the peritoneal environment controls the differentiation of macrophage precursors, committing them toward an alternatively activated, reparatory phenotype. In turn, alternatively activated macrophages are necessary for ectopic lesions to vascularize and grow.…”

Soluble M6P/IGF2R Released by TACE Controls Angiogenesis via Blocking Plasminogen Activation

“…Based on these findings, we assume that the CD11b ϩ cells could be a subset of dendritic cells. Strikingly, dendritic cells have been shown to play an important role in regulation of angiogenesis 34,35 and, similarly to endothelial cells, do use the uPA/Plg system to migrate. 36 Second, we studied the effect of peptide 18 -36 on tumor growth in a chimeric in vivo model by growing human melanoma cells in SCID mice: the human melanoma M24met cells were injected into the right flank of an animal and at the same time an osmotic pump filled with either scrambled peptide or peptide 18-36 was implanted at a distal position in the same flank.…”

PI3Kγ Activates Integrin α4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression

“…Defects in DCs caused by the immunosuppressive tumor microenvironment result in the accumulation of immature DCs. These immature DCs can promote tumor angiogenesis (28)(29)(30)(31)(32)(33)(34)(35)(36) and suppress T-cell responses (10), thus favoring tumor progression. We observed that blockade of a PI3Kg-integrin a 4 pathway could facilitate CD11c þ DC infiltration and maturation.…”