Orchestration of angiogenesis by immune cells

Abstract

It is widely accepted that the tumor microenvironment (TUMIC) plays a major role in cancer and is indispensable for tumor progression. The TUMIC involves many "players" going well beyond the malignant-transformed cells, including stromal, immune, and endothelial cells (ECs). The non-malignant cells can acquire tumor-promoting functions during carcinogenesis. In particular, these cells can "orchestrate" the "symphony" of the angiogenic switch, permitting the creation of new blood vessels that allows rapid expansion and progression toward malignancy. Considerable attention within the context of tumor angiogenesis should focus not only on the ECs, representing a fundamental unit, but also on immune cells and on the inflammatory tumor infiltrate. Immune cells infiltrating tumors typically show a tumor-induced polarization associated with attenuation of anti-tumor functions and generation of pro-tumor activities, among these angiogenesis. Here, we propose a scenario suggesting that the angiogenic switch is an immune switch arising from the pro-angiogenic polarization of immune cells. This view links immunity, inflammation, and angiogenesis to tumor progression. Here, we review the data in the literature and seek to identify the "conductors" of this "orchestra." We also suggest that interrupting the immune → inflammation → angiogenesis → tumor progression process can delay or prevent tumor insurgence and malignant disease.

Keywords: angiogenesis; angiogenic switch; immune cells; inflammation.

Figure 1

Inflammatory orchestration of tumor angiogenesis. Both solid and hematological malignancies are associated with an inflammatory state characterized by different innate and adaptive immune cells. These cells are able to play two different symphonies at the same: on one hand they can contribute to tumor suppression and eradication, on the other they play a key role in tumor insurgence and progression. The TUMIC produces several factors, including TGFβ, PGE2, VEGF, lactic acid, and adenosine, which contribute to polarization of immune cells toward a pro-tumor/pro-angiogenic phenotype. Polarization is not only mediated by tumor cell products, but also involves crosstalk between immune cells. Ag–Ab, antigen–antibody complexes; CSCs, cancer stem cells.