Introduction: Prostate cancer is hormone dependent and regulated by a balance of androgens as well as estrogens. Regulatory control is also exerted by the tumor microenvironment including cancer-associated fibroblasts (CAFs), and immune cells. Although patient derived xenografts (PDX) commonly used to study the functional effects of CAFs, the method is not quantitative, is lengthy, technically challenging and the xenografts are placed in immune suppressed hosts excluding immune cell contribution.
Methods: We developed a novel bioengineered cellularized co-culture to study stromal-immune cell interactions. Our novel system quantifies multiple cellular interactions between human tumour stromal fibroblasts and mast cells on epithelial tumour cell morphology, motility and invasion.
Results: First we show mast cell numbers are increased in human PCa clinical specimens, specifically within the peri-tumoural stroma. Using our bioengineered cultures we next show CAFs induce morphological changes in epithelial cells independent of the Gleason grade of the tumor of origin. However, when human mast cells were also added to the co-culture system, there was further and significant potentiation of the effects of CAFs on epithelial cells features. Further mechanistic studies showed estrogen (via ERalpha) mediates cooperation between CAFs and mast cells at the tumour interface. Human mast cells express ERα and ERβ, and estradiol directly stimulates mast cell proliferation and migration as well as altered cytokine/chemokine expression. Androgen signaling is reduced in CAFs, while ERα and ERβ transcriptional activity is not, allowing estrogen to dictate hormone action in the tumor microenvironment. Gene microarray analyses identified CXCL12 as a major estrogen driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner.
Conclusions: Collectively, these data reveal multicellular estrogen action in the tumormicroenvironment and show dominant estrogen signaling at the prostatic tumor interface.
03 - 07 May 2014
European Society of Endocrinology