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SU‐E‐J‐105: Stromal‐Epithelial Responses to Fractionated Radiotherapy
Author(s) -
Qayyum M
Publication year - 2014
Publication title -
medical physics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 180
eISSN - 2473-4209
pISSN - 0094-2405
DOI - 10.1118/1.4888157
Subject(s) - stromal cell , stroma , radiation therapy , fibroblast , cancer research , cell growth , breast cancer , cancer cell , cancer associated fibroblasts , pathology , cancer , cell culture , chemistry , biology , medicine , immunohistochemistry , biochemistry , genetics
Purpose: The stromal‐epithelial‐cell interactions that are responsible for directing normal breast‐tissue development and maintenance play a central role in the progression of breast cancer. In the present study, we developed 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 postsurgical treatment. Methods: Cancerous human mammary epithelial cells were cultured in a 3‐D collagen matrix with human fibroblasts stimulated by various concentrations of transforming growth factor beta 1 (TGF‐β1). These culture samples were designed to model the post‐lumpectomy mammary stroma in the presence of residual cancer cells. We tracked over time the changes in medium stiffness, fibroblast‐cell activation (conversion to cancer activated fibroblasts (CAF)), 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 fibroblasts and CAF that higher doses per fraction may be more effective early on in deactivating cancer‐harboring cellular environments. Higher‐dose fraction schemes inhibit contractility in CAF and prevent differentiation of fibroblasts, thereby metabolically uncoupling tumor cells from their surrounding stroma. Yet, over a longer time period, the higher dose fractions may slow wound healing and increase ECM stiffening that could stimulate proliferation of surviving cancer cells. Conclusion: The findings suggest that dose escalation to the region with residual disease can deactivate the reactive stroma, thus minimizing the cancer promoting features of the cellular environment. Large‐fraction irradiation may be used to sterilize residual tumor cells and inhibit activation of intracellular transduction pathways that are promoted during the post‐surgical woundhealing period. NIH award R01CA138882