Abstract
Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.
Highlights
The organization of animal tissues is maintained by communication of epithelial cells with each other and the surrounding cellular and non-cellular stromal components
We focus on the role of the tumor microenvironment (TME), and in particular of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) proteins, during prostate homeostasis, benign prostatic hyperplasia, prostatic intraepithelial lesions, primary Prostate cancer (PCa), and bone metastasis in order to elucidate the stromal contribution in different prostate disease contexts
Organ-confined PCa is amenable to curative treatments, including surgery, androgen-deprivation therapies (ADT), radiation, and active surveillance
Summary
The organization of animal tissues is maintained by communication of epithelial cells with each other and the surrounding cellular and non-cellular stromal components. CAFs establish of primary PCa tissue samples is typically characterized by lower calponin and desmin expression, a paracrine communication with cancer cells through the release of factors such as IL-6, IL-8, TGFβ, FGFs, increased vimentin staining (due to the high number of fibroblasts, especially CAFs) and VEGF, and GDF15, stimulating tumor growth, angiogenesis, and progression. Examples of factors released by CAFs are TGF-β, fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), interleukin-6 (IL-6), and growth differentiation factor 15 (GDF15) [32,40,41]
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