Fibroblast growth factor-2 mediates transforming growth factor-β action in prostate cancer reactive stroma

Yang, Feng Chun; Strand, Douglas W.; Rowley, David R.

doi:10.1038/sj.onc.1210663

Cited by 79 publications

(71 citation statements)

References 30 publications

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“…In early tumor lesions, aberrant FGF-2 production and expression of its receptor (FGFR1) can alter the epithelial/stromal communication, which ensures the balance between growth and renewal of the epithelial compartment under physiological conditions (KwabiAddo et al, 2004). Moreover, FGF-2 production by both stromal and tumor cells promotes increased proliferation and metastasis formation in prostate cancer (PCa) (Cronauer et al, 1997;Giri et al, 1999;Yang et al, 2008). Thus, the FGF-2/FGFR axis is an attractive target for cancer therapy, in terms of both ligand sequestration and receptor inhibition (Smith et al, 2001;He et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

et al. 2011

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The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

et al. 2011

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“…The major source of FGFs is the stromal compartment in the normal prostate. A balanced interaction between stromal and epithelial cells through FGFs, which act as paracrine growth factors for epithelial cells, is crucial for normal development and growth of prostate epithelium (Tuxhorn et al 2002, Ayala et al 2003, Yang et al 2008. FGF-2 supports proliferation, migration and invasion in human prostate cancer cellular models (Wesley et al 2005).…”

Section: Introductionmentioning

confidence: 99%

SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling

Puhr¹,

Santer²,

Neuwirt³

et al. 2010

Endocrine-Related Cancer

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Fibroblast growth factor-2 (FGF-2) is highly expressed in prostate cancer. It promotes tumour progression through multiple pathways including those of signal transducers and activators of transcription factor 3 (STAT3), mitogen-activated protein kinases (MAPKs) and Akt. In previous studies, we have reported that STAT3 phosphorylation inversely correlates with suppressor of cytokine signalling-3 (SOCS-3) expression in prostate cancer cells. Recently, it has become evident that SOCS-3-negative regulation is not only limited to the interleukin-6 (IL-6) receptor. We hypothesised that SOCS-3 interferes with FGF signalling, thus influencing the outcome of its action in prostate cancer cells. For this purpose, we treated DU-145 and LNCaP-IL-6C cells with increasing concentrations of FGF-2, and verified protein phosphorylation. In the presence of FGF-2, neither STAT3, STAT1, nor Akt could be phosphorylated. Solely the p44/p42 MAPK pathway was activated after FGF-2 stimulation. We show for the first time that SOCS-3 interferes with the FGF-2 signalling pathway by modulating p44 and p42 phosphorylation in prostate cancer cells. Decreased SOCS-3 protein expression results in increased MAPK phosphorylation, whereas SOCS-3 overexpression leads to a decreased cellular proliferation and migration. On the basis of the present results, we propose that SOCS-3 is a novel modulator of FGF-2-regulated cellular events in prostate cancer.

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“…Importantly, the volume of reactive stroma relative to cancer is predictive of the rate of cancer progression in several tumor types (8)(9)(10)(11)(12)(13)(14)(15). Furthermore, in vivo modeling has shown that reactive stroma is tumor-promoting (16)(17)(18)(19). The myofibroblast is the principal cell type in reactive stroma, and transforming growth factor beta 1 (TGF-β1) is a potent inducer of myofibroblast differentiation (3,20).…”

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confidence: 99%

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

Kim

Barron²,

Martin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

131

126

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Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate-derived mesenchymal stem cells (MSCs) and the TGF-β1-regulated pathways that modulate MSC proliferation and myofibroblast differentiation. Human prostate MSCs combined with prostate cancer cells expressing TGF-β1 resulted in commitment to myofibroblasts. TGF-β1-regulated runt-related transcription factor 1 (RUNX1) was required for cell cycle progression and proliferation of progenitors. RUNX1 also inhibited, yet did not block, differentiation. Knockdown of RUNX1 in prostate or bone marrow-derived MSCs resulted in cell cycle arrest, attenuated proliferation, and constitutive differentiation to myofibroblasts. These data show that RUNX1 is a key transcription factor for MSC proliferation and cell fate commitment in myofibroblast differentiation. This work also shows that the normal human prostate gland contains tissue-derived MSCs that exhibit multilineage differentiation similar to bone marrow-derived MSCs. Targeting RUNX1 pathways may represent a therapeutic approach to affect myofibroblast proliferation and biology in multiple disease states. myofibroblast | MSC | RUNX1 | TGF-β1 | reactive stroma

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Fibroblast growth factor-2 mediates transforming growth factor-β action in prostate cancer reactive stroma

Cited by 79 publications

References 30 publications

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

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