Stromal-Epithelial Interaction in Prostate Cancer Progression

Chung, Leland W.K.; Huang, Wen-Chin; Sung, Shian Ying; Wu, Daqing; Odero-Marah, Valerie; Nomura, Takeo; Shigemura, Katsumi; Miyagi, Tohru; Seo, Seogil; Shi, Chumeng; Molitierno, Joe; Elmore, James M.; Anderson, C.; Isotani, Shuji; Edlund, Magnus; Hsieh, Chia Ling; Wang, Ruoxiang; Shehata, Bahig M.; Zhau, Haiyen E.

doi:10.3816/cgc.2006.n.034

Cited by 75 publications

(59 citation statements)

References 112 publications

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“…5D) and fatty acid levels (data not shown) in prostate cancer cells. These data are consistent with previous reports and in aggregate reveal that ␤2M is a pleiotropic signaling molecule (6,7,36) and has a triad relationship with SREBP-1 and AR, which determines the growth and survival of prostate cancer cells. ␤2M-mediated signaling is important for the maintenance of SREBP-1 expression and SREBP-1 regulates AR expression and prostate cancer cell growth and survival (Fig.…”

Section: A Triad Relationship Among ␤2m Srebp-1 and Ar Is Involved supporting

confidence: 82%

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Huang

Zhau

Chung

2010

Journal of Biological Chemistry

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A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-␤2-microglobulin monoclonal antibody (␤2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. ␤2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, ␤2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, ␤2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the ␤2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing ␤2M by ␤2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression. ␤2-Microglobulin (␤2M)3 is a co-receptor of a major histocompatibility complex class I antigen. ␤2M has been implicated in the regulation of the host immune mechanism and is essential for the recognition of foreign antigens by T-lymphocytes (1). Recent reports from our laboratory and others assigned additional biological functions to ␤2M as a diagnostic and prognostic indicator for multiple myeloma, prostate, and breast cancers (2-5); a growth factor and a signaling molecule (6, 7); a new androgen and androgen receptor (AR) target gene (8); and an attractive new therapeutic target for both liquid (9) and solid (10, 11) tumor malignancies. Blockade of ␤2M and its related signaling pathways by sequence-specific siRNA or antibody resulted in the inhibition of AR expression and activity and the induction of extensive prostate cancer cell death in vitro as well as prostate tumor regression in immune-compromised mice (7, 10). In addition, anti-␤2M monoclonal antibody (␤2M mAb) has been shown not to significantly affect the growth of normal cells, consistent with experimental observations where transgenic mice with a ␤2M deficit had normal organ function and life expectancy (9, 10, 12). Therefore, ␤2M and its signaling axis may offer an opportunity for improving the clinical targeting of prostate cancer.AR is a key growth and survival regulatory transcription factor for androgen target organs during normal development and neoplastic progression. Recognition of the importance of the AR signaling axis, particularly in castration-resistant prostate cancer, has prompted discoveries targeting androgen biosynthetic pathways using abiraterone as an agent for a Phase III trial...

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Section: A Triad Relationship Among ␤2m Srebp-1 and Ar Is Involved supporting

confidence: 82%

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Huang

Zhau

Chung

2010

Journal of Biological Chemistry

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“…It has been widely recognized that the tumor microenvironment plays a major role in dictating tumor behavior and progression, as well as response to therapy (Lubaroff et al, 1980;Chung, 1993;Pettaway et al, 1996;Singh et al, 2007). Indeed, mammary stromal fibroblasts have been shown both in vitro and in vivo to modulate mammary carcinoma cell proliferation (Brouty-Boye and Raux, 1993;Sadlonova et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Artemin is oncogenic for human mammary carcinoma cells

et al. 2009

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We report that artemin, a member of the glial cell linederived neurotrophic factor family of ligands, is oncogenic for human mammary carcinoma. Artemin is expressed in numerous human mammary carcinoma cell lines. Forced expression of artemin in mammary carcinoma cells results in increased anchorage-independent growth, increased colony formation in soft agar and in three-dimensional Matrigel, and also promotes a scattered cell phenotype with enhanced migration and invasion. Moreover, forced expression of artemin increases tumor size in xenograft models and leads to highly proliferative, poorly differentiated and invasive tumors. Expression data in Oncomine indicate that high artemin expression is significantly associated with residual disease after chemotherapy, metastasis, relapse and death. Artemin protein is detectable in 65% of mammary carcinoma and its expression correlates to decreased overall survival in the cohort of patients. Depletion of endogenous artemin with small interfering RNA, or antibody inhibition of artemin, decreases the oncogenicity and invasiveness of mammary carcinoma cells. Artemin is therefore oncogenic for human mammary carcinoma, and targeted therapeutic approaches to inhibit artemin function in mammary carcinoma warrant consideration.

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“…The environmental influence is especially apparent in prostate cancer in that bone is by far the most common site of metastasis (14). The propensity of prostate cancer to metastasize to bone suggests that interactions between the metastatic prostate cancer cells and the tumor microenvironment are important in the progression of prostate cancer (15)(16)(17)(18). Delineating the mechanisms involved in promoting metastatic prostate tumor progression in the bone will lead to better treatment strategies for bone metastasis.…”

Section: Introductionmentioning

confidence: 99%

Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells

Cheng

Vakar-López³

et al. 2007

Molecular Cancer Research

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ErbB-3, an ErbB receptor tyrosine kinase, has been implicated in the pathogenesis of several malignancies, including prostate cancer. We found that ErbB-3 expression was up-regulated in prostate cancer cells within lymph node and bone metastases. Despite being a plasma membrane protein, ErbB-3 was also detected in the nuclei of the prostate cancer cells in the metastatic specimens. Because most metastatic specimens were from men who had undergone androgen ablation, we examined the primary tumors from patients who have undergone hormone deprivation therapy and found that a significant fraction of these specimens showed nuclear localization of ErbB3. We thus assessed the effect of androgens and the bone microenvironment on the nuclear translocation of ErbB-3 by using xenograft tumor models generated from bone-derived prostate cancer cell lines, MDA PCa 2b, and PC-3. In subcutaneous tumors, ErbB-3 was predominantly in the membrane/cytoplasm; however, it was present in the nuclei of the tumor cells in the femur. Castration of mice bearing subcutaneous MDA PCa 2b tumors induced a transient nuclear translocation of ErbB-3, with relocalization to the membrane/cytoplasm upon tumor recurrence. These findings suggest that the bone microenvironment and androgen status influence the subcellular localization of ErbB-3 in prostate cancer cells. We speculate that nuclear localization of ErbB-3 may aid prostate cancer cell survival during androgen ablation and progression of prostate cancer in bone. (Mol Cancer Res 2007;5(7):675 -84)

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Stromal-Epithelial Interaction in Prostate Cancer Progression

Cited by 75 publications

References 112 publications

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Artemin is oncogenic for human mammary carcinoma cells

Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells

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