A bioengineered microenvironment to quantitatively measure the tumorigenic properties of cancer-associated fibroblasts in human prostate cancer

作者：Clark Ashlee K; Taubenberger Anna V; Taylor Renea A; Niranjan Birunthi; Chea Zhen Y; Zotenko Elena; Sieh Shirly; Pedersen John S; Norden Sam; Frydenberg Mark; Grummet Jeremy P; Pook David W; Stirzaker Clare; Clark Susan J; Lawrence Mitchell G; Ellem Stuart J; Hutmacher Dietmar W; Ri**ridger Gail P^*

来源：Biomaterials, 2013, 34(20): 4777-4785.

DOI：10.1016/j.biomaterials.2013.03.005

• Prostate cancer
• Cancer-associated fibroblasts
• Tumor stroma
• In vitro model
• Co-culture
• Extracellular matrix (ECM)

Stromal-epithelial cell interactions play an important role in cancer and the tumor stroma is regarded as a therapeutic target. In vivo xenografting is commonly used to study cellular interactions not mimicked or quantified in conventional 2D culture systems. To interrogate the effects of tumor stroma (cancer-associated fibroblasts or CAFs) on epithelia, we created a bioengineered microenvironment using human prostatic tissues. Patient-matched CAFs and non-malignant prostatic fibroblasts (NPFs) from men with moderate (Gleason 7) and aggressive (Gleason 8-9 or castrate-resistant) prostate cancer were cultured with non-tumorigenic BPH-1 epithelial cells. Changes in the morphology, motility and phenotype of BPH-1 cells in response to CAFs and NPFs were analyzed using immunofluorescence and quantitative cell morphometric analyses. The matrix protein gene expression of CAFs, with proven tumorigenicity in vivo, had a significantly different gene expression profile of matrix proteins compared to patient matched NPFs. In co-culture with CAFs (but not NPFs), BPH-1 cells had a more invasive, elongated phenotype with increased motility and a more directed pattern of cell migration. CAFs from more aggressive tumors (Gleason 8-9 or CRPC) were not quantitatively different to moderate grade CAFs. Overall, our bioengineered microenvironment provides a novel 3D in vitro platform to systematically investigate the effects of tumor stroma on prostate cancer progression.

• 出版日期2013-7