Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Verona, Erik V.; Elkahloun, Abdel G.; Yang, Junhua; Bandyopadhyay, Abhik; Yeh, I‐Tien; Sun, LuZhe

doi:10.1158/0008-5472.can-07-0444

Cited by 75 publications

(61 citation statements)

References 45 publications

(57 reference statements)

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“…As an in vivo experimental model, several groups have demonstrated that coinoculation of commercialized human prostatic stromal cells (PrSC) with human PCa cells increased tumorigenicity in terms of tumor incidence and tumor growth (Uemura et al 2005, Verona et al 2007). In addition, Kawada et al (2006) have shown that the PrSC-conditioned medium increased the cell proliferation of human PCa cells in vitro, suggesting that the secreted factors from PrSC-regulated tumor growth in vivo.…”

Section: Discussionmentioning

confidence: 99%

Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo

Ishii

Imamura²,

Iguchi³

et al. 2009

Endocrine-Related Cancer

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Activation of tumor-stromal interactions is considered to play a critical role in the promotion of tumorigenesis. To discover new therapeutic targets for hormone-refractory prostate tumor growth under androgen ablation therapy, androgen-sensitive LNCaP cells and the derived sublines, E9 (androgen-low-sensitive), and AIDL (androgen-insensitive), were recombined with androgendependent embryonic rat urogenital sinus mesenchyme (UGM). Tumors of E9CUGM and AIDLCUGM were approximately three times as large as those of LNCaPCUGM. Tumors grown in castrated hosts exhibited reduced growth as compared with those in intact hosts. However, in castrated hosts, E9CUGM and AIDLCUGM tumors were still approximately twice as large as those of LNCaPCUGM. Cell proliferation in tumors of E9CUGM and AIDLCUGM grown in castrated host, was significantly higher than that in tumors of LNCaPCUGM. In vitro, expression of fibroblast growth factor (FGF)-2 and IGF-I, but not FGF-7 mRNA, was significantly reduced in UGM under androgen starvation. In cell culture, E9 cells were responsive to FGF-2 and FGF-7 stimulation, while AIDL responded to FGF-7 and IGF-1. Expression of FGFR1 and FGFR2 was considerably higher in E9 than those in LNCaP, similarly expression of FGFR2 and IGF-IR were elevated in AIDL. These data suggest that activation of prostate cancer cell growth through growth factor receptor expression may result in the activity of otherwise androgenindependent stromal growth factor signals such as FGF-7 under conditions of androgen ablation.

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Section: Discussionmentioning

confidence: 99%

Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo

Ishii

Imamura²,

Iguchi³

et al. 2009

Endocrine-Related Cancer

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“…This stromal reaction is an early feature common to many malignant epithelial neoplasms initiated via the action of cancer cell-derived secreted factors, in particular transforming growth factor b1, that modify the surrounding stroma generating a microenvironment which in turn further supports tumor growth and progression (Barclay et al 2005, Ao et al 2007, Verona et al 2007, Sampson et al 2011. The tumorassociated 'reactive' stroma is characterized in particular by activation of fibroblasts but also by recruitment of inflammatory cells, ECM remodeling and enhanced angiogenesis.…”

Section: Benign and Carcinoma-associated Prostate Stromal Cellsmentioning

confidence: 99%

In vitro model systems to study androgen receptor signaling in prostate cancer

Sampson

Neuwirt

Puhr

et al. 2013

Endocrine-Related Cancer

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Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic.

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“…The normal prostate has an abundance of stromal components, mainly well-differentiated smooth muscle cells. In prostate tumors, however, fibroblasts surrounding cancer cells are associated not only with the initiation of cancer cells but also with tumor growth and progression to androgen independence (11)(12)(13). Olumi et al demonstrated stroma-induced malignant transformation, indicating that fibroblasts surrounding epithelia play an important role in PCa development (14).…”

Section: Introductionmentioning

confidence: 99%

“…Olumi et al demonstrated stroma-induced malignant transformation, indicating that fibroblasts surrounding epithelia play an important role in PCa development (14). Other groups reported that coinoculation of PCa cells with fibroblasts increased tumorigenicity and implied the promotion of angiogenesis (11,15,16). Therefore, the inhibition of tumor-stroma interactions with addition of the suppression of cancer cell growth might lead to synergistic effects on tumor control.…”

Section: Introductionmentioning

confidence: 99%

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

Hori

Ishii

Kanda

et al. 2011

Cancer Prevention Research

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In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha 1 -adrenoceptor (a 1 -AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G 1 cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective a 1 -AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and a 1 -AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G 1 cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells.

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Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Cited by 75 publications

References 45 publications

Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo

Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo

In vitro model systems to study androgen receptor signaling in prostate cancer

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

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