Role of stroma in carcinogenesis of the prostate

Departments of Anatomy and Urology, University of California, San Francisco, CA 94143-0452, USA.
Differentiation (Impact Factor: 3.44). 01/2003; 70(9-10):473-85. DOI: 10.1046/j.1432-0436.2002.700902.x
Source: PubMed


Prostatic development is induced by androgens acting via mesenchymal-epithelial interactions. Androgens elicit their morphogenetic effects by acting through androgen receptors (ARs) in urogenital sinus mesenchyme (UGM), which induces prostatic epithelial development. In adulthood reciprocal homeostatic stromal-epithelial interactions maintain functional differentiation and growth-quiescence. Testosterone plus estradiol (T+E2) have been shown to induce prostatic carcinogenesis in animal models. Thus, tissue recombinant studies were undertaken to explore the mechanisms of prostatic carcinogenesis in BPH-1 cells in which ARs and estrogen receptors (ERs) are undetectable. For this purpose, BPH-1 cells were combined with UGM, and the UGM+BPH-1 recombinants were grafted to adult male hosts. Solid branched epithelial cords and ductal structures formed in untreated UGM+BPH-1 recombinants. Growth was modest, and tumors did not develop. UGM+BPH-1 recombinants treated with T+E2 formed invasive carcinomas. BPH-1 cells lack ARs and ERs, whereas rat UGM expresses both of these receptors. These data show that immortalized nontumorigenic human prostatic epithelial cells can undergo hormonal carcinogenesis in response to T+E2 stimulation via paracrine mechanisms and demonstrate that the stromal environment plays an important role in mediating hormonal carcinogenesis. During prostatic carcinogenesis the stroma undergoes progressive loss of smooth muscle with the appearance of carcinoma-associated fibroblasts (CAF). This altered stroma was tested for its ability to promote carcinogenesis of nontumorigenic but immortalized human prostatic epithelial cells (BPH-1). CAF+BPH-1 tissue recombinants formed large carcinomas. In contrast, recombinants composed of normal prostatic stroma+BPH-1 cells exhibited minimal growth. This stroma-induced malignant transformation was associated with additional genetic alterations and changes in gene expression. Thus, alteration in the stromal microenvironment was sufficient to promote malignant transformation of human prostatic epithelial cells.

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    • "Many early studies have shown that these bone marrow cells set up a metastatic niche at the secondary site that allows for cells to establish [1] [2]. Subsequent studies have specifically isolated myeloid-derived suppressor cells [3] [4] [5] [6], myofibroblast [7] [8] [9], and tumor-associated macrophages [10] [11] [12]. Each of these has some overlapping roles in metastasis, but each class of cells is a distinct bone marrow cell type with distinct roles in metastasis (summarized in Figure 1). "
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    BioMed Research International 06/2014; 2014(11):875305. DOI:10.1155/2014/875305 · 2.71 Impact Factor
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    • "Taking this into consideration, we can say that the finasteride treatment influenced both the androgenic and angiogenic pathways. Estrogenic effects in the prostate are the results of the binding of these hormones to specific α and β estrogen receptors (ER-α, ER-β), which are predominantly expressed in the stroma and epithelium, respectively (Cunha et al., 2002). Candido et al. (2012) found an increased ER-α reactivity in the prostate of senile rats submitted to both androgen ablation and to the administration of estrogen and testosterone. "
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    • "The stroma is complex consisting of smooth muscle cells, fibroblasts, blood vessels, nerves, inflammatory cells and so on. The pioneering work from Dr. Cunha's laboratory has demonstrated that stroma plays a critical role in the development, function, and carcinogenesis of the prostate.89 The epithelial compartment of the prostate has three cell types: (i) secretory cells (or luminal cells) that produce secreted proteins including prostate-specific antigen (PSA), (ii) basal cells that likely function as reserve cells and (iii) neuroendocrine (NE) cells101112 that have neuronal morphology and endocrine function. "
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