Figure 2.

Tumor microenvironment. Tumor tissue is characterized by a high cellular density that hampers oxygen and nutrient perfusion. Accordingly, cancer cells are genetically and epigenetically heterogeneous, and those located far from the blood vessels: (1) favor an anaerobic metabolism that leads to the environment acidification; (2) are more resistant to pharmacological treatments because of their low division rate and genetic instability [42]. Fibroblasts and pericytes are responsible for tissue remodeling, while the immunosuppressive milieu hinders immune cell activity. NCs extravasation and penetration are mainly limited by solid stress and high interstitial fluid pressure, which in certain areas may reach values close to the aortic pressure [43].