Importance of critical metabolites and cellular interactions in the biology of microregions of tumors.

Heterogeneity of cellular microenvironments and associated differences in phenotypic expression of cells in solid tumors occur as a consequence of deficiencies of vascularization. Intervascular microregions of tumors and micrometastases can be modeled by multicellular spheroids in vitro. These develop concentration gradients of critical metabolites such as oxygen, glucose, and probably also other important nutrients, hormones, and growth factors. Drug penetration may also be reduced. Concentrations of these factors decrease from the periphery towards the center, but gradients develop in the opposite direction for certain metabolic and necrotic products such as lactate and pH. Such gradients significantly modify the proliferative status of the cells, viability, clonogenicity, cell cycle distribution, antigen expression, and differentiation. Stress of oxygen and glucose deprivation induces synthesis of a specific set of proteins. Cellular interactions can also modulate phenotypic expression, including oxygen and glucose consumption rates and sensitivity to radiation and drugs. The mechanisms of these are unknown, but changes in cell-cell communication and DNA damage and repair have been demonstrated in spheroids. Microenvironmental and cellular changes may be transient. Thus, the characteristics of cells in tumor microregions may be quite different from the intrinsic cellular properties observed after growth of cells in standard culture systems. These changes may have significant effects on responses to therapeutic agents.