scholarly journals Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate

2013 ◽  
Vol 304 (11) ◽  
pp. E1131-E1139 ◽  
Author(s):  
Alejandro S. Godoy ◽  
Ivy Chung ◽  
Viviana P. Montecinos ◽  
Ralph Buttyan ◽  
Candace S. Johnson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Endothelial Cells ◽  
Tumor Growth ◽  
Vascular Function ◽  
Tumor Vasculature ◽  
Prostate Tumor ◽  
Antiangiogenic Agents ◽  
Vitamin D Receptors ◽  
Published Evidence

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients.

scholarly journals Elimination of Vitamin D Receptor in Vascular Endothelial Cells Alters Vascular Function

Hypertension ◽  
2014 ◽  
Vol 64 (6) ◽  
pp. 1290-1298 ◽  
Author(s):  
Wei Ni ◽  
Stephanie W. Watts ◽  
Michael Ng ◽  
Songcang Chen ◽  
Denis J. Glenn ◽  
...  
Keyword(s):  
Vitamin D ◽  
Endothelial Cells ◽  
Vitamin D Receptor ◽  
Vascular Function ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial

scholarly journals Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1405
Author(s):  
Zhichao Zhou ◽  
Yuanzheng Yang ◽  
Fei Wang ◽  
Eugenie S. Kleinerman
Keyword(s):  
Tumor Growth ◽  
Ewing Sarcoma ◽  
Vascular Function ◽  
Fusion Gene ◽  
Critical Role ◽  
Survival Rates ◽  
Tumor Vasculature ◽  
Tumor Growth And Metastasis

Survival rates for Ewing sarcoma (ES) patients with metastatic disease have not improved in over 20 years. Tumor growth and metastasis are dependent on tumor vasculature expansion; therefore, identifying the regulators that control this process in ES may provide new therapeutic opportunities. ES expresses high levels of repressor element 1 silencing transcription factor (REST), which is regulated by the EWS-FLI-1 fusion gene. However, the role of REST in ES growth and the regulation of the tumor vasculature have not been elucidated. To study this role, we established REST-knockout human TC71 ES cell lines through CRISPR/Cas9 recombination. While knockout of REST did not alter tumor cell proliferation in vitro, REST knockout reduced tumor growth and metastasis to the lung in vivo and altered tumor vascular morphology and function. Tumor vessels in the REST-knockout tumors had a punctate appearance with significantly decreased tumor vascular pericytes, decreased perfusion, and increased permeability. REST-knockout tumors also showed increased apoptosis and hypoxia. These results indicate that REST plays a critical role in ES vascular function, which in turn impacts the ability of ES tumors to grow and metastasize. These findings therefore provide a basis for the targeting of REST as a novel therapeutic approach in ES.

Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies

2002 ◽  
Vol 20 (18) ◽  
pp. 3906-3927 ◽  
Author(s):  
Frank A. Scappaticci
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Endothelial Cells ◽  
Tumor Vasculature ◽  
Resistance Mechanisms ◽  
Antiangiogenic Agents ◽  
Cancer Therapies ◽  
Future Directions ◽  
New Strategy ◽  
And Control

ABSTRACT: Targeting angiogenesis represents a new strategy for the development of anticancer therapies. New targets derived from proliferating endothelial cells may be useful in developing anticancer drugs that prolong or stabilize the progression of tumors with minimal systemic toxicities. These drugs may also be used as novel imaging and radiommunotherapeutic agents in cancer therapy. In this review, the mechanisms and control of angiogenesis are discussed. Genetic and proteomic approaches to defining new potential targets on tumor vasculature are then summarized, followed by discussion of possible antiangiogenic treatments that may be derived from these targets and current clinical trials. Such strategies involve the use of endogenous antiangiogenic agents, chemotherapy, gene therapy, antiangiogenic radioligands, immunotherapy, and endothelial cell-based therapies. The potential biologic end points, toxicities, and resistance mechanisms to antiangiogenic agents must be considered as these therapies enter clinical trials.

scholarly journals Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1Expression

2000 ◽  
Vol 275 (32) ◽  
pp. 24500-24505 ◽  
Author(s):  
Jeremy R. Graff ◽  
Bruce W. Konicek ◽  
Ann M. McNulty ◽  
Zejing Wang ◽  
Keith Houck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Prostate Tumor ◽  
Prostate Cancer Progression

scholarly journals Estrogen exhibits a biphasic effect on prostate tumor growth through the ERβ-KLF5 pathway

2015 ◽  
pp. MCB.00625-15 ◽  
Author(s):  
Yuka Nakajima ◽  
Asami Osakabe ◽  
Tsuyoshi Waku ◽  
Takashi Suzuki ◽  
Kensuke Akaogi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Prostate Tumor ◽  
Biphasic Effect ◽  
New Strategy ◽  
17Β Estradiol ◽  
Xenograft Models

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol, E2) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly,in vivoangiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc-finger transcription factor 5 (KLF5). In addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits pro-apoptoticFOXO1and pro-angiogenicPDGFAexpression. Furthermore, we revealed that a non-agonistic ER ligand GS-1405 inhibitedFOXO1andPDGFA expression through ERβ and KLF5 pathway, and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

Kallistatin is a new inhibitor of angiogenesis and tumor growth

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3245-3252 ◽  
Author(s):  
Robert Q. Miao ◽  
Jun Agata ◽  
Lee Chao ◽  
Julie Chao
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Gene Delivery ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Vascular Function ◽  
Hind Limb ◽  
Heparin Binding

Abstract Kallistatin is a unique serine proteinase inhibitor (serpin) and a heparin-binding protein. It has been localized in vascular smooth muscle cells and endothelial cells of human blood vessels, suggesting that kallistatin may be involved in the regulation of vascular function. Our previous study showed that kallistatin plays a role in neointima hyperplasia. In this study, we investigated the potential role of kallistatin in angiogenesis in vitro and in vivo. Purified human kallistatin significantly inhibited vascular endothelial growth factor (VEGF)– or basic fibroblast growth factor (bFGF)–induced proliferation, migration, and adhesion of cultured endothelial cells. Kallistatin attenuated VEGF- or bFGF-induced capillary density and hemoglobin content in subcutaneously implanted Matrigel plugs in mice. To further investigate the role of kallistatin in angiogenesis, we prepared adenovirus carrying the human kallistatin cDNA (Ad.HKBP) and evaluated the effect of kallistatin gene delivery on spontaneous angiogenesis in a rat model of hind-limb ischemia. Local kallistatin gene delivery significantly reduced capillary formation and regional blood perfusion recovery in the ischemic hind limb after removal of the femoral artery. Furthermore, a single intratumoral injection of Ad.HKBP into pre-established human breast tumor xenografts grown in athymic mice resulted in significant inhibition of tumor growth. CD31 immunostaining of tumor sections showed a decreased number of blood vessels in the kallistatin-treated group as compared to the control. These results demonstrate a novel role of kallistatin in the inhibition of angiogenesis and tumor growth.

scholarly journals Differential expression of protein disulfide-isomerase A3 isoforms, PDIA3 and PDIA3N, in human prostate cancer cell lines representing different stages of prostate cancer

2021 ◽  
Author(s):  
Maria Araceli Diaz Cruz ◽  
Sandra Karlsson ◽  
Ferenc Szekeres ◽  
Maria Faresjö ◽  
Dan Lund ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Mrna Expression ◽  
Cell Lines ◽  
Protein Function ◽  
Protein Disulfide Isomerase ◽  
Expression Ratio ◽  
Disulfide Isomerase ◽  
Vitamin D Receptors ◽  
Protein Disulfide

AbstractProstate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression.

scholarly journals Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

2020 ◽  
Author(s):  
Yuyi Wang ◽  
Ombretta Salvucci ◽  
Hidetaka Ohnuki ◽  
Andy D. Tran ◽  
Taekyu Ha ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Tyrosine Kinases ◽  
Vascular Endothelial Cells ◽  
Tyrosine Phosphatase ◽  
Tumor Hypoxia ◽  
Blood Perfusion ◽  
Tumor Vasculature ◽  
Immune Checkpoints ◽  
Tumor Vascularity

AbstractThe tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumors selected for SHP2-independent tumor-cell growth, promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor hypoxia and necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints or recruiting anti-tumor macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/Tie2 inhibitors hold promise to effectively target the tumor endothelium.

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