The CCN Family of Angiogenic Regulators: The Integrin Connection

Lau, Lester F.; Lam, Stephen

doi:10.1006/excr.1999.4456

Cited by 602 publications

(616 citation statements)

References 85 publications

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“…with hormone-dependent breast cancer including angiogenesis (7,10); however, the alteration of Cyr61 expression has been demonstrated to be associated with a number of pathologies (11)(12)(13), including malignant neoplasms (14,15). In previous studies by our group, Cyr61 expression profiling in BC and its functional expression regulation was examined (16,17) demonstrating a stage-dependent induction of Cyr61 in BC tumorigenesis and hypoxia-induced alternative splicing of Cyr61 in tumor cells.…”

Section: Clinical Relevance Of Cyr61 Expression In Patientsmentioning

confidence: 97%

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

et al. 2017

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Abstract. Tumor resistance to endocrine therapy triggers estrogen-independent cancer progression, which is a major obstacle to the successful treatment of hormone receptor positive breast cancer (BC). The underlying molecular mechanisms of endocrine resistance are not fully understood yet. The matricellular protein cysteine-rich angiogenic inducer 61 (Cyr61) is associated with tumor invasiveness and the induction of tumorigenesis in various malignancies in vivo and the induction of estrogen-independence and endocrine therapy resistance in BC. The present study evaluated the potential effects and clinical relevance of Cyr61 expression levels in 67 patients with primary non-metastatic BC. Immunohistochemical analysis of formalin-fixed paraffin-embedded tissue sections was performed, and the association between Cyr61 protein expression and clinicopathological factors and survival was analyzed. Cyr61 overexpression was revealed to be significantly associated with a positive estrogen receptor (ER)/progesterone receptor (PR) status (P=0.016) and to the molecular subtype of BC (P=0.039). Compared with patients without Cyr61 overexpression, patients with Cyr61 overexpression exhibited an increased recurrence rate (30.6 vs. 22.6%) and decreased long-term survival (10-year overall survival, 62.9 vs. 69.7%); however, these associations did not reach statistically significant levels in Cox regression model analysis. Similar results were identified in the subgroup analysis of patients with ER/PR positive BC. These results indicate that Cyr61 serves a role in the development of endocrine therapy resistance in BC and is thus a potential therapeutic target to overcome endocrine therapy resistance. However, additional long-term survival analyses with large patient populations are required.

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Section: Clinical Relevance Of Cyr61 Expression In Patientsmentioning

confidence: 97%

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

et al. 2017

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“…Among the genes that we found to be regulated at hypoxia by DNA array analysis, we identified the angiogenesis gene CCN1 whose secreted protein contributes to cellular proliferation, differentiation, and angiogenesis (25)(26)(27). CCN1 expression is elevated in a range of tumors (24).…”

Section: Creb-mediated Regulation Of Ccn1 At Hypoxia Mol Cancer Res 2mentioning

confidence: 99%

“…The immediate early gene CCN1 (CYR61), a member of the CCN family, codes for a secreted heparin binding protein associated with the cell surface and extracellular matrix (23). Functionally, CCN1 promotes cell adhesion, proliferation, migration, and angiogenesis through cell type -specific binding to different integrins (24)(25)(26)(27). Changes in CCN1 expression have been associated with several cancer types (28,29).…”

Section: Introductionmentioning

confidence: 99%

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Meyuhas¹,

Pikarsky²,

Tavor³

et al. 2008

Molecular Cancer Research

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Hypoxia is a prominent feature of solid tumors known to contribute to malignant progression and therapeutic resistance. Cancer cells adapt to hypoxia using various pathways, allowing tumors to thrive in a low oxygen state. Induction of new blood vessel formation via the secretion of proangiogenic factors is one of the main adaptive responses engaged by tumor cells under hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a pivotal role in mediating such responses. In addition, several other transcription factors have also been implicated in hypoxic gene regulation, either independently or in cooperation with HIF-1. In this work, we show that the expression of the angiogenesis-related, immediate early gene CCN1 (formerly known as CYR61), considered to be involved in tumor growth and invasiveness, is enhanced upon hypoxia stress primarily in a protein kinase A and cyclic AMP-responsive element binding protein (CREB) and CRE -dependent manner in various cell lines. The hypoxia-mediated activation of the CCN1 promoter is independent of HIF-1 and HIF-2, as shown by small interfering RNA knockdown. We identify the cis element in the mouse CCN1 promoter responsible for CREB binding to be one of two partial CRE sites present in the promoter. Moreover, we report for the first time that CREB-mediated CCN1 transcription is enhanced in hypoxic regions of tumors in vivo. Identifying and characterizing the molecular mechanisms that govern the response of tumors to hypoxia may be instrumental to identify the tumors that will respond favorably to inhibition of angiogenesis and thus lead to the development of treatments that could complement hypoxia-inducing treatment modalities.

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“…1-3). The CCN proteins are multifunctional and are involved in cell adhesion, angiogenesis, cell differentiation, and tumorigenesis (4)(5)(6)(7)(8). CTGF was first identified as a mitogen from human umbilical vein endothelial cells, and expression of CTGF is inducible by tumor growth factor-h in fibroblasts (9).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Chien¹,

Ding²,

Gui

et al. 2006

Molecular Cancer Research

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Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non -small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G 0 -G 1 and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I -dependent Akt phosphorylation and epidermal growth factordependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.

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The CCN Family of Angiogenic Regulators: The Integrin Connection

Cited by 602 publications

References 85 publications

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

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