Molecular Insights Into Prostate Cancer Progression: The Missing Link of Tumor Microenvironment

Chung, Leland W.K.; Baseman, Adam G.; Assikis, Vasily J.; Zhau, Haiyen E.

doi:10.1097/01.ju.0000141582.15218.10

Cited by 313 publications

(268 citation statements)

References 59 publications

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“…These findings suggest that the biological impact of NMU expression on tumor formation is highly related to the tumor microenvironment. This is consistent with the evidence that tumor-microenvironment Neuromedin U enhances lung metastasis Y Wu et al interactions affect local cancer growth, invasion and metastasis (Chung et al, 2005). NMU can also induce the release of inflammatory cytokines in T helper-2 (Th2)-type T cells, mast cells or macrophages (Johnson et al, 2004;Moriyama et al, 2005Moriyama et al, , 2006.…”

Section: Discussionsupporting

confidence: 89%

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and nonmetastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.

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Section: Discussionsupporting

confidence: 89%

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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“…Collagen I is a heterotrimeric, fibrillar protein that is the major structural extracellular protein in most tissues (Chung et al, 2005). Collagen I has been the most extensively examined collagen in aged hosts and the consensus is that ageing confers a progressive decrease in collagen I synthesis at the same time there is an increase in collagen I degradation.…”

Section: Extracellular Matrixmentioning

confidence: 99%

Extracellular influences on tumour angiogenesis in the aged host

2008

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Whether tumours are epithelial or non-epithelial in origin, it is generally accepted that once they reach a certain size all solid tumours are dependent upon a vascular supply to provide nutrients. Accordingly, there is great interest in how the extracellular environment enhances or inhibits vascular growth. In this minireview, we will examine key extracellular components, their changes with ageing, and discuss how these alterations may influence the subsequent development of tumour vasculature in the aged host. Because of the tight correlation between advanced age and development of prostate cancer, we will use prostate cancer as the model throughout this review.

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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%

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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Molecular Insights Into Prostate Cancer Progression: The Missing Link of Tumor Microenvironment

Cited by 313 publications

References 59 publications

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

Extracellular influences on tumour angiogenesis in the aged host

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

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