BACKGROUND: The stromal-epithelial-cell interactions that are responsible for directing normal breast-tissue development and maintenance play a central role in the progression of @entity0 . In the present study, we continued our development of three-dimensional (3-D) cell co-cultures used to study cancerous mammary cell responses to fractionated radiotherapy. In particular, we focused on the role of the reactive stroma in determining the therapeutic ratio for post-surgical treatment. METHODS: Cancerous @entity1 mammary epithelial cells (MRC-7) were cultured in a 3-D collagen matrix with @entity1 fibroblasts (MRC-5) stimulated by various concentrations of @entity2533 ( @entity2533 ). These culture samples were designed to model the post-lumpectomy mammary stroma in the presence of @entity5 cells. We tracked over time the changes in medium stiffness, fibroblast-cell activation (MRC-5 converted to @entity5 activated fibroblasts (CAFs)), and proliferation of both cell types under a variety of fractionated radiotherapy protocols. Samples were exposed to 6 MV X-rays from a linear accelerator in daily fraction sizes of 90, 180 and 360  cGy over five days in a manner consistent with irradiation exposure during radiotherapy. RESULTS: We found in fractionation studies with MRC-5 fibroblasts and CAFs that higher doses per fraction may be more effective early on in deactivating @entity5 -harboring cellular environments. Higher-dose fraction schemes inhibit contractility in CAFs and prevent differentiation of fibroblasts, thereby metabolically uncoupling @entity5 cells from their surrounding stroma. However, higher dose fraction appears to increase ECM stiffening. CONCLUSIONS: The findings suggest that dose escalation to the region with residual disease can deactivate the reactive stroma, thus minimizing the @entity5 promoting features of the cellular environment. Large-fraction irradiation may be used to sterilize @entity41 cells and inhibit activation of intracellular transduction pathways that are promoted during the post-surgical wound-healing period. The higher dose fractions may slow wound healing and increase ECM stiffening that could stimulate proliferation of surviving @entity5 cells.

Stromal-epithelial responses to fractionated radiotherapy in a XXXX microenvironment.

@entity1 :: ('9606', 'Species') :: ['human'] @entity0 :: ('MESH:D001943', 'Disease') :: ['breast cancer'] @entity41 :: ('MESH:D018365', 'Disease') :: ['residual tumor'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'residual cancer', 'cancer'] @entity2533 :: ('7040', 'Gene') :: ['TGF-b1', 'transforming growth factor beta 1']
@entity0 :: (MESH:D001943,Disease) :: ['breast cancer']
