Mesenchymal Stem Cells: Differential Interaction with Tumor Parenchyma which relies on the tumor type and on the source of mesenchymal cells.

BOLONTRADE, MARCELA F., CAFFERATA, EDUARDO A., ROTONDARO, CECILIA, KLEIN, GRACIELA, CANEPA, CARLOS O., PODHAJCER, OSVALDO L.

La Jolla, California.

Conferencia; AACR Special Conference, “Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications” , American Association for Cancer Research (AACR).; 2005

American Association for Cancer Research (AACR).

Breast carcinomas are desmoplastic tumors, with tumor stroma accounting for more than 90 percent of the tumor mass. Complex interactions between tumor stroma and parenchyma allows for the development of a stroma permissive for the expansion of the tumor cells and for further stroma development, since the quality of the supportive tissue changes to allow for the growth and migration of endothelial cells, fibroblasts and blood cells into the tumor. The genetic model for breast cancer states that cancer development proceeds through a multistep model in which epithelial cells undergo transformation as a result of multiple genetic hits. Nevertheless, evidence suggests that the tumor stroma suffers concomitant changes, and as a result of this, tumor progression proceeds through a permissive tumor stroma (epigenetic model). The presence of a large supportive stroma in breast cancer and the complex interactions between breast tumor stroma and breast cancer cells makes stromal cells an attractive target for therapy. Adult human Mesenchymal stem Cells (MSCs) are non-hematopoietic cells, which can be isolated mainly from adult bone marrow and from peripheral blood. Differentiation pathways in MSCs are not strictly delineated, since even apparently fully differentiated cells have the potential to convert into another lineage. Thus, plasticity is a major characteristic of the MSC system. These cells have a high proliferative capacity and possess selective tropism to tumor areas, where they can differentiate into various tumor stromal components, including tumor fibroblasts. Thus, the contribution of non-local mesenchymal cells to tumor stroma may not only be in terms of providing cellular support for the expanding stroma but of providing a differential quality, that in turn would add to the permissive properties of tumor stroma. The role of mesenchymal stem cells obtained from different  sources has not yet been explored in terms of its selective affinity for the tumor parenchyma. Thus, we have analyzed bone marrow-derived mesenchymal stem cells and perypheral blood mesenchymal cells, at various stages of differentiation, to assess for the degree of interaction with breast cancer epithelial cells as a desmoplastic tumor model, and melanoma cells as a non-desmoplastic tumor stroma model. Using multilamellar spheroids to study parenchyma-stroma interaction, our results show that heterotypic breast cancer spheroids made of malignant and mesenchymal cells were best compacted in the presence of perypheral blood-derived mesenchymal cells, with a low culture passage. On the contrary, in heterotypic melanoma spheroids, the best levels of spheroid compactation were achieved with bone marrow-derived mesenchymal cells; this is indicative of a differential biological behavior of mesenchymal cells as a component of tumor stroma, which depends both on their source and on the tumor parenchyma. This promising novel results will bring particular insight on in vivo studies and potential clinical implications with the use of mesenchymal cells as vehicles for tumor treatment.