Dendritic Cell Subsets Differentially Regulate Angiogenesis in Human Ovarian Cancer

Abstract

Angiogenesis is essential for both primary and metastatic tumor growth. Tumor blood vessel formation is complex and regulated by many factors. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites of patients with untreated ovarian carcinoma. We observed high numbers of plasmacytoid dendritic cells (PDCs) and significant stromal-derived factor (CXCL-12/SDF)-1 in their malignant ascites, attracting PDCs into the tumor environment. We now show that tumor-associated PDCs induced angiogenesis in vivo through production of tumor necrosis factor ␣ and interleukin 8. By contrast, myeloid dendritic cells (MDCs) were absent from malignant ascites. MDCs derived in vitro suppressed angiogenesis in vivo through production of interleukin 12. Thus, the tumor may attract PDCs to augment angiogenesis while excluding MDCs to prevent angiogenesis inhibition, demonstrating a novel mechanism for modulating tumor neovascularization. Because dendritic cells (DCs) have long been known to affect tumor immunity, our data also implicate DCs in regulation of tumor neoangiogenesis, suggesting a novel role of DCs in tumor pathology.

Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes

“…Since type I IFN inhibit proliferation of certain tumors, their role has also been studied in the immune response to cancer cells [20,24,[30][31][32][33][34][35].…”

The immune network in thyroid cancer

“…55 Tumor-associated DCs release VEGF-A, CXCL8/IL-8 and osteopontin. 56 Human eosinophils promote angiogenesis 57 and eosinophilia can be observed in ATC patients. 58 Tregs play a role in maintaining tolerance in TC and drive tumor angiogenesis through the release of VEGF-A.…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…The involvement of dendritic cells in tumor angiogenesis has recently drawn major attention. It is thought that mature myeloid DCs suppress tumor angiogenesis and thereby impede both tumor growth and metastasis by secreting or stimulating the production of anti-angiogenic factors, such as IL-12, IFNg and IL-10 [240]. Conversely, the tumor-induced suppression of myeloid DC maturation described above therefore enhances tumor angiogenesis.…”

“…Conversely, the tumor-induced suppression of myeloid DC maturation described above therefore enhances tumor angiogenesis. Moreover, tumors contain significant numbers of plasmacytoid and vascular DCs secreting pro-angiogenic molecules, such as TNFa and IL-8 [230,240,241]. Based on this rather complex situation, the involvement of DCs in tumor angiogenesis and metastasis and their therapeutic exploitation certainly deserves future investigation.…”