Abstract:To analyze effects of cellular interaction between human mesenchymal stroma/stem cells (MSC) and different cancer cells, direct co-cultures were performed and revealed significant growth stimulation of the tumor populations and a variety of protein exchanges. More than 90% of MCF-7 and primary human HBCEC699 breast cancer cells as well as NIH:OVCAR-3 ovarian adenocarcinoma cells acquired CD90 proteins during MSC co-culture, respectively. Furthermore, SK-OV-3 ovarian cancer cells progressively elevated CD105 an… Show more
“…34,49–51 CytoB has been well-studied and used extensively for negative controls in in vitro studies of TNTs, due to its ability to destabilize actin. We used this drug at doses similar to previous studies which demonstrate its ability to prevent formation 49,52 or disrupt 53 TNTs. In our assay, CytoB was added at the same time as NV1066 virus; as compared with no drug, the addition of CytoB led to >50% reduction in cell death; the increase in amount of cell death when GCV was also added was minimal, indicating that the role of potential non-TNT transfer of viral TK-activated GCV through the membrane filter was minimal.…”
Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir. Using confocal microscopy we assessed the ability of TNTs to propagate enhanced green fluorescent protein (eGFP), which is encoded by the herpes simplex virus NV1066, from infected to uninfected recipient cells. Using time-lapse imaging, we observed eGFP expressed in infected cells being transferred via TNTs to noninfected cells; additionally, increasing fluorescent activity in recipient cells indicated cell-to-cell transmission of the eGFP-expressing NV1066 virus had also occurred. TNTs mediated cell death as a form of direct cell-to-cell transfer following viral thymidine kinase mediated activation of ganciclovir, inducing a unique long-range form of the bystander effect through transmission of activated ganciclovir to nonvirus-infected cells. Thus, we provide proof-of-principle demonstration of a previously unknown and alternative mechanism for inducing apoptosis in noninfected recipient cells. The conceptual advance of this work is that TNTs can be harnessed for delivery of oncolytic viruses and of viral thymidine kinase activated drugs to amplify the bystander effect between cancer cells over long distances in stroma-rich tumor microenvironments.
“…34,49–51 CytoB has been well-studied and used extensively for negative controls in in vitro studies of TNTs, due to its ability to destabilize actin. We used this drug at doses similar to previous studies which demonstrate its ability to prevent formation 49,52 or disrupt 53 TNTs. In our assay, CytoB was added at the same time as NV1066 virus; as compared with no drug, the addition of CytoB led to >50% reduction in cell death; the increase in amount of cell death when GCV was also added was minimal, indicating that the role of potential non-TNT transfer of viral TK-activated GCV through the membrane filter was minimal.…”
Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir. Using confocal microscopy we assessed the ability of TNTs to propagate enhanced green fluorescent protein (eGFP), which is encoded by the herpes simplex virus NV1066, from infected to uninfected recipient cells. Using time-lapse imaging, we observed eGFP expressed in infected cells being transferred via TNTs to noninfected cells; additionally, increasing fluorescent activity in recipient cells indicated cell-to-cell transmission of the eGFP-expressing NV1066 virus had also occurred. TNTs mediated cell death as a form of direct cell-to-cell transfer following viral thymidine kinase mediated activation of ganciclovir, inducing a unique long-range form of the bystander effect through transmission of activated ganciclovir to nonvirus-infected cells. Thus, we provide proof-of-principle demonstration of a previously unknown and alternative mechanism for inducing apoptosis in noninfected recipient cells. The conceptual advance of this work is that TNTs can be harnessed for delivery of oncolytic viruses and of viral thymidine kinase activated drugs to amplify the bystander effect between cancer cells over long distances in stroma-rich tumor microenvironments.
“…Several of the molecular mechanisms and biochemical pathways involved in MSC–solid tumor cross-talk have been extensively reviewed recently [112]. Here, we should point out that in these processes the exosomes released by MSC play a key role [113,114]. For instance, MSC-derived exosomes can influence the fate of nasopharyngeal carcinoma by modifying the expression of EMT markers [115].…”
Section: Msc Cross-talk With Tumor Cellsmentioning
The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.
“…1 and 2, respectively. Several direct and/or indirect mechanisms of interaction contribute to MSC-mediated stimulation of cancer cell growth including Notch signaling, nanotube formation, gap junctional intercellular communication, and/or the exchange of cytokines/chemokines, extracellular vesicles and exosomes [36–38]. It is thus important to emphasize that these different types of indirect and direct interactions are always multidirectional, therefore affecting and altering both, the tumor cells as well as the MSC or other cellular partners.Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Co-culture of MSC with cancer cells like breast or ovarian cancer at certain conditions in vitro can lead to the development of hybrid cells by fusion of the two parental cell lines [38]. Potential fusion events depend on the cell density, the cell ratio of the parental populations, the medium components and culture conditions (ionic strength, pH, hypoxia) among others.…”
Section: Introductionmentioning
confidence: 99%
“…In co-culture models of MSC populations together with different kinds of breast and ovarian tumor cells, MSC increase the proliferation of cancer cells [38]. Multiple cellular interactions between MSC and breast cancer cells are accompanied by increased growth of breast cancer both in vitro and in vivo [72] including MSC-mediated induction of CD90 expression in the tumor cells.…”
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.
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