Role of MSC in the Tumor Microenvironment

Abstract

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor's metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.

Keywords: cell fusion; cell interaction; extracellular matrix; mesenchymal stroma-/stem-like cells; tumor microenvironment.

Figure 1

Different processes between MSC and cancer cells within the tumor stroma are mediated indirectly via the exchange of chemokines/cytokines, growth factors, metabolites such as PGE2 and exosomes/microvesicles. Certain restructuring of the ECM by proteases and the production of matrix proteins can form transient compartments to enable (1) metastasis by EMT and the trans-endothelial migration of disseminating cancer cells in tumor vessels displaying an abnormal physiology due to aberrant pericyte coverage and leaky endothelial cell layers; (2) cancer cell growth and inhibition by the contribution of CA⁺-MSC and CA⁻-MSC; (3) the formation of dynamic CSCNs for the generation, expansion and maintenance of CSCs; and (4) cancer hybrid cell formation by MSC–cancer cell entosis or cell fusion (adapted from [82]).