Fig. 1.

Main participants of tumor heterogeneity and the complex cellular milieu in tumor tissue. a Many different factors influence tumor development in correlation with the hallmarks of cancer. In the last century, terminology relating to tumor tissue heterogeneity was introduced. Each type of heterogeneity has been extensively studied; based on these, the figure describes the associated areas of cancer research. The summarized “heterogeneity section” consists of subcategories including cellular elements, genetic diversity, immune, microenvironmental, and metabolic alterations of the tumor (these main elements and their contributors are indicated). The shown heterogeneities in the sector contribute to the individual phenotypes, which constitute the complex ecosystem (with tumor and non-tumorous cells in tissue structure). Stress and starving conditions influence tissue heterogeneity and cellular proliferation, differentiation, and survival mechanisms. Unfortunately, evolutionary mechanisms may select highly aggressive cell populations in the developing ecosystem, contributing to disease relapse or metastasis in patients. (APCs, antigen-presenting cells; NKs, natural killer cells; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; CSC, cancer stem cell; CAFs, cancer-associated fibroblasts; ECM, extracellular matrix). b Metabolic complexity of the tumor tissue in correlation with vascularization. The altered concentrations of glucose-lactate, oxygen-ROS (reactive oxygen species), H⁺ (pH)-metabolic waste, and amino acids (essential and nonessential amino acids — EAAs/NEAAs); and their altering gradients are labeled with blue/red triangles. The labeling of different cellular elements and other matrix components are also indicated