Interaction of MSC with tumor cells

Abstract

Tumor development and tumor progression is not only determined by the corresponding tumor cells but also by the tumor microenvironment. This includes an orchestrated network of interacting cell types (e.g. immune cells, endothelial cells, fibroblasts, and mesenchymal stroma/stem cells (MSC)) via the extracellular matrix and soluble factors such as cytokines, chemokines, growth factors and various metabolites. Cell populations of the tumor microenvironment can interact directly and indirectly with cancer cells by mutually altering properties and functions of the involved partners. Particularly, mesenchymal stroma/stem cells (MSC) play an important role during carcinogenesis exhibiting different types of intercellular communication. Accordingly, this work focusses on diverse mechanisms of interaction between MSC and cancer cells. Moreover, some functional changes and consequences for both cell types are summarized which can eventually result in the establishment of a carcinoma stem cell niche (CSCN) or the generation of new tumor cell populations by MSC-tumor cell fusion.

Keywords: Cell fusion; Cellular interaction; MSC; Mesenchymal stroma/stem cells; Tumor cell signaling; Tumor microenvironment.

Fig. 1

Indirect interactions between mesenchymal stroma/stem cells and cancer cells. a Cytokines, chemokines, growth factors: MSC secrete a plethora of soluble factors that can bind as substrates to appropriate receptors on the cell surface of cancer cells and vice versa for mutual activation of signaling pathways. b Metabolites: Likewise, MSC-released metabolites such as prostaglandin E2, kynurenine or galectin-1 can act in a paracrine manner on cancer cells altering their properties and functions [14]. c Exosomes: Both, MSC and cancer cells, secrete exosomes for the exchange of small molecules including protein, mRNAs and microRNAs. d Microvesicles: Besides exosomes, microvesicles represent a different type of microparticles for the exchange of small molecules such as mRNAs or microRNAs affecting tumor cells and MSC in mutual ways

Fig. 2

Direct interactions between mesenchymal stroma/stem cells and cancer cells. a Notch signaling: A prominent example for direct cell-to-cell interaction is represented by Notch signaling. DAPT, a Notch signaling inhibitor, was shown to decrease functional alterations of breast cancer cells after co-culture with MSC underlining the involvement of Notch signaling in MSC-cancer cell interactions. b GJIC: Both MSC and cancer cells build gap junctions for intercellular communication. Gap junctional intercellular communication (GJIC) can be inhibited by gap junction inhibitor carbenoxolone (CBX) resulting in lesser interactions and functional alterations of cancer cells and MSC. c Nanotube formation: Long and thin plasma membrane structures formed between MSC and cancer cells allow the transport of small molecules and organelles for cellular cross-talk leading to altered functions and phenotype. d Trogocytosis: An exchange of whole plasma membrane fragments via an active transfer outlines a further possible interaction type between MSC and cancer cells resulting in structural and functional alterations of the recipient cell. e Cell fusion: In rare cases, mesenchymal stem cells have the capacity to fuse with various cancer cell types such as breast, ovarian, lung and gastric cancer cells. The molecular mechanism about the formation of such cancer hybrid cells is still unknown

Fig. 3

Formation and culture of tumor hybrid cells after spontaneous cell fusion. a Co-culture of MSC^GFP with MDA-MB-231^cherry breast cancer cells demonstrating the development of fusion cells which are indicated by white arrows. Scale bars represent 200 μM. b Mono-culture of isolated and expanded MDA-hybrid2 cells exhibiting dual fluorescence from both maternal cell populations (MSC^GFP and MDA-MB-231^cherry). Scale bars represent 100 μM