Abstract 1012: A liquid miscibility model of tumor-stromal interaction in prostate cancer

Preventing the spread of prostate cancer would significantly reduce the morbidity and mortality associated with this disease. Impeding the interaction between tumor and normal cells is a possible strategy for therapeutic intervention. The prostate gland contains two distinct compartments, epithelial and stromal. In aggressive prostate cancer the boundary between these compartments disappears, allowing tumor cells to intermix with stromal cells. Intermixing facilitates access of tumor cells to blood and lymphatic vessels, facilitating invasion and subsequent metastasis. Understanding the molecular and physical forces driving intermixing is a crucial first step in preventing the spread of prostate cancer. We present a model in which prostate cancer cell-stromal cell interaction can be viewed as a liquid miscibility/immiscibility phenomenon, rooted in the same thermodynamic principles that govern the interactions between simple liquids. The premise is that whether cancer and stromal cells remain segregated or intermix depends on their relative strength of self- and cross-adhesion. We apply an analogy of the high energy interaction between ethanol and water resulting in miscibility (intermixing) of the two phases, or the lower energy of interaction between oil and water resulting in immiscibility (segregation), to test the hypothesis that the model can differentiate between such interactions in mixtures of prostate cancer and stromal cells. We show that when differentially-labeled non invasive AT-2 or invasive MLL cells are mixed with rat prostatic fibroblasts (RPF), AT-2 cells segregate from RPF cells, while MLL cells remain intermixed, suggesting that the MLL-RPF interaction is of higher energy than that of AT-2 and RPF. A switch in the composition of the prostatic stroma from smooth muscle (SMCs) to fibroblastic is a hallmark of malignant transformation in prostate cancer. We mixed MLL cells either with rat prostatic SMCs or RPF cells and showed that MLL cells segregate from SMCs but intermix with fibroblasts. This indicates that MLL cells have higher affinity for prostatic fibroblasts than for SMCs and is consistent with the observation that the stroma of more aggressive prostate cancers is predominantly fibroblastic. Invasive CaP cells lack the ability to assemble a fibronectin matrix. We have previously shown that restoring this ability gives rise to increased cohesion between cells in 3D spheroids. We treated MLL cells with MEK inhibitors (MEKi) and showed that treatment restored the ability of MLL cells to assemble fibronectin into a fibrillar matrix, leading to increased cell-cell cohesion. When mixed with RPF cells MEKi-treated MLL segregated, suggesting that altering the cohesive relationship between tumor cells is sufficient to reduce their affinity for stromal cells. Our model provides a molecular and physical basis for exploring epithelial-stromal interaction in an easily-manipulated in vitro system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1012.