The stroma plays a key role in maintenance of tissue homeostasis. A reactive stroma evolves early in the progression of prostate cancer. One way reactive stroma remodels the microenvironment is by deposition of tenascin-C. Tenascin-C is an extracellular matrix protein that is expressed during development and is critical for neuronal patterning and osteogenesis. In contrast, expression of tenascin C in adult tissues is limited and is restricted to regions of wound repair, tissue remodeling and pathological conditions, such as cancer.

To assess whether the bone exhibits a reactive tissue phenotype in the context of metastasis, human prostate cancer metastasis tissue arrays were evaluated using immunohistochemistry and spectral deconvolution. This work identified a tenascin-C expression pattern at trabeculae-associated metastatic sites, suggesting the evolution of a reactive endosteum.

In order to evaluate the mechanisms involved, we developed an in vitro 3D osteogenic organoid, using human mesenchymal stem cells induced to osteoblastic differentiation, which exhibits a reactive endosteum phenotype. Co-culture with the metastatic prostate cancer cell line VCaP showed preferential binding at sites high in tenascin C deposition. Also, metastatic cells were capable of adherence to purified tenascin C in vitro, forming 3D colonies. We have identified α9β1 integrin as a mediator of prostate cancer cell adhesion to tenascin C-rich surfaces. Preliminary data has also identified signaling through WNK1 and STAT6 as additional candidate mechanisms that mediate tenascin-C induced biology in prostate cancer cells that are metastatic to bone surfaces.

These studies characterize a reactive endosteum phenotype at sites of metastatic prostate cancer foci and suggest that elevated tenascin-C at these sites mediates the adhesive and other biological properties of cancer cells. This study will help provide data from which to develop novel therapeutic approaches to treat metastatic disease.

Citation Format: Rebeca San Martin, David R. Rowley, Kenneth J. Pienta. Tenascin C as an effector of prostate cancer derived bone metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2268. doi:10.1158/1538-7445.AM2015-2268