[Angiogenesis and immune suppression: yin and yang of tumor progression?]

Specialized variants of neoplastic cells that appear in tumors during cancer disease progression possess the ability to recruit certain kinds of hematopoietic and mesenchymal cells from the bone marrow or bloodstream. These tumor-recruited hematopoietic cells include monocytes, macrophages, granulocytes, mast and dendritic cells, as well as myeloblastic suppressor cells. Fibroblasts derived from undifferentiated mesenchymal cells are also recruited. Some of these cells (especially macrophages and fibroblasts) then undergo "education-like" phenotype reprogramming under the influence of the neoplastic cell population, resulting in the appearance of tumor-associated macrophages (TAM) and fibroblasts (CAF). Together with the extracellular matrix (ECM) as well with the remaining types of recruited cells, they contribute to the formation of a specific tumor microenvironment. Both the cells forming the tumor microenvironment and neoplastic cells engage in the two intimately linked processes of angiogenesis and immune suppression. The network of defective blood vessels formed during tumor angiogenesis and the resulting fluctuations in blood flow lead to under-oxygenation of the surrounding neoplastic cells and have substantial impact on their metabolic profile. A number of processes triggered in these under-oxygenated neoplastic cells appear to strongly favor further tumor progression. Such processes result in lower oxygen demand, enhanced angiogenesis, and epithelial-mesenchymal transition, owing to which the neoplastic cells acquire the ability to translocate. Under-oxygenation also leads to augmented genetic instability of the neoplastic cells. The tumor environment-forming cells also have their share in the establishment of an immunosuppressive environment which enables the neoplastic cells to escape immune surveillance. By providing a sophisticated milieu for the selection of increasingly malignant neoplastic cells (i.e. with proangiogenic and immunosuppressive phenotypes), the tumor microenvironment-forming cells substantially contribute to the progression of a neoplasm. Inhibited angiogenesis thus makes an immune response, both nonspecific and specific, possible. The remarks presented here may prove helpful in devising novel anticancer strategies involving antiangiogenic in combination with immunomodulatory drugs.