Growth Factor Signaling Axis Research Articles

Effect of CHRDL1 on angiogenesis and metastasis of colorectal cancer cells via TGF-β/VEGF pathway.

Colorectal cancer (CRC) is a common digestive tract tumor with the third incidence and death in the world. There is still an urgent need for effective therapeutic targets and prognostic markers for CRC. Herein, we report a novel potential target and marker, Chordin like-1 (CHRDL1). The function of CHRDL1 has been reported in gastric cancer, breast cancer, and oral squamous cell carcinoma. However, the biological effect of CHRDL1 in CRC remains unrevealed. Transwell and tube formation experiments were used to determine the biological function of CHRDL1. Western blot and rescue experiments were used to determine the specific mechanisms of CHRDL1. Results showed CHRDL1 is significantly downregulated in CRC cell lines and tissues. In vitro, experiments confirmed that CHRDL1 can inhibit cell growth, migration, invasion, angiogenesis and reverse epithelial-mesenchymal transformation. In vivo, experiments proved that it can inhibit tumor growth and metastasis. Mechanistically, we newly find that CHRDL1 exerts biological functions through the transforming growth factor-beta (TGF-β)/vascular endothelial growth factor signaling axis in vitro and in vivo. Therefore, we concluded that CHRDL1 reduces the growth, migration, and angiogenesis of CRC cells by downregulating TGF-β signaling. Our new findings on CHRDL1 may provide a basis for clinical antiangiogenesis therapy and the prognosis of CRC.

TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis.

The kinase TBK1 responds to microbial stimuli and mediates type I interferon (IFN-I) induction. We show that TBK1 is also a central mediator of growth factor signaling; this function relies on a specific adaptor, TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to PKCθ via a scaffold protein, Card10, which allows PKCθ to phosphorylate TBK1 at serine-716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. While the TBK1/TBKBP1 signaling axis is dispensable for IFN-I induction, it mediates mTORC1 activation and oncogenesis. Lung epithelial cell-conditional deletion of either TBK1 or TBKBP1 inhibits tumorigenesis in a mouse model of lung cancer. In addition to promoting tumor growth, the TBK1/TBKBP1 axis facilitates tumor-mediated immunosuppression by a mechanism involving induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signaling axis mediating both tumor growth and immunosuppression.

Clinical and experimental study of matrix metalloproteinase-9/angiotensin/vascular endothelial growth factor signaling axis in diabetic foot

Objective To investigate the role of matrix metalloproteinase-9/angiostatin/vascular endothelial growth factor signal axis in diabetic foot (DF) disease. Methods Immunofluorescence staining, Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) and Western blotting were used to detect the messenger RNA (mRNA) and protein expression level of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in normal and the foot wound tissues of DF patients. Human umbilical vein endothelial cells (HUVECs) were selected as the study subjects. The experiment was divided into 4 groups: normal control group; high glucose (25 mmol/L) model group; high glucose + anti-MMP-9 (5 μg/ml) group and high glucose + anti-angiostatin (5 μg/ml) group. The cell culture supernatant and a part of cells were collected at 12, 24 and 48 h, respectively. The secretion and expression of VEGF were detected by enzyme-linked immunosorbent assay (ELISA), RT-qPCR and Western blotting. Results The results of clinical samples showed that MMP-9 was highly expressed in the tissues of DF patients with foot wounds compared with normal subjects(mRNA level: P=0.000; protein level: P=0.000). However, VEGF showed significant low expression in the tissues of DF patients with foot wounds(mRNA level: P=0.003; protein level: P=0.000). The results of cell experiments showed that compared with the normal group at 12, 24, 48h, the VEGF secretion and mRNA and protein expression level of in the high glucose group were significantly decreased (secretion level: P=0.032, 0.006, 0.004; mRNA level: P=0.003, 0.000, 0.000; protein level: P=0.000, 0.000, 0.000); However, compared with the high glucose group, the VEGF secretion and mRNA and protein levels of the two treatment groups were significantly increased (anti-MMP-9 secretion level: P=0.041, 0.003, 0.000; mRNA level: P=0.039, 0.006, 0.005; protein level: P=0.089, 0.042, 0.037; anti-angiostatin secretion level: P=0.005, 0.001, 0.000; mRNA level: P=0.004, 0.001, 0.000; protein level: P=0.031, 0.001, 0.000), and it was time-dependent. Conclusion The expression of MMP-9 in the DF patients is negatively correlated with the expression of VEGF. The inhibition of MMP-9 and angiostatin can significantly promote the VEGF secretion and expression in HUVECs induced by high glucose, which will provide theoretical basis on clinical treatment for DF. Key words: Matrix metalloproteinase-9; Angiostatin; Vascular endothelial growth factor; Diabetic foot

Correction: Absence of the Full-Length Breast Cancer-Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members.

Correction: Absence of the Full-Length Breast Cancer-Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members.

Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

Erratum: Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members (Cancer Research (July 15, 2006) 66 (7151-7157))

Erratum: Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members (Cancer Research (July 15, 2006) 66 (7151-7157))

Novel TIE-2 inhibitor BAY-826 displays invivo efficacy in experimental syngeneic murine glioma models.

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation invitro and invivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model.

Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.

Insulin-like growth factor I receptor β expression in hepatocellular carcinoma

The insulinlike growth factor signaling axis (factors I and II and their receptor) has been implicated in hepatocarcinogenesis. Previous studies on insulinlike growth factor I receptor using resected hepatocellular carcinoma generated mixed results; however, the distribution and clinical significance of insulinlike growth factor I receptor β expression in hepatocellular carcinoma in the setting of liver transplantation have not been evaluated. Immunohistochemical staining for insulinlike growth factor I receptor β was performed in 72 liver explants from patients with hepatocellular carcinoma undergoing liver transplantation. Expression of insulinlike growth factor I receptor β in hepatocytes was noted in 59.7% of tumors but only 6.9% of adjacent, nontumorous liver tissues (P < .001). Compared with subjects with tumors within Milan criteria, those who fell beyond had 3.1 times higher odds of having insulinlike growth factor I receptor β-positive tumors (95% confidence interval, 1.003-9.8). Poorly differentiated hepatocellular carcinomas had 10.3 times higher odds of insulinlike growth factor I receptor β positivity compared with well- or moderately differentiated tumors (95% confidence interval, 1.3-85.2). Subjects with nonalcoholic steatohepatitis were less likely to have insulinlike growth factor I receptor β-positive tumors (P = .015). Finally, higher arteriolar insulinlike growth factor I receptor β scores in the tumor and adjacent liver were significantly associated with insulinlike growth factor I receptor β expression in tumor cells (P = .015 and .043 for intratumoral and adjacent arterioles, respectively) in a subset of 26 randomly chosen hepatocellular carcinoma. Our results suggest that synchronized up-regulation of the insulinlike growth factor I receptor axis in tumor cells and intratumoral and adjacent arterioles could represent a mechanism of hepatocarcinogenesis and progression as manifest by poor differentiation and tumors beyond Milan criteria. Targeted therapies against insulinlike growth factor receptors may be justifiable in the treatment of hepatocellular carcinoma.

450: A Novel B2-Microglobulin/Protein Kinase A/Vascular Endothelial Growth Factor Signaling Axis Promotes Human Renal Cell Carcinoma Growth and Bone Metastasis

You have accessJournal of UrologyPodium 15, Sunday, May 20, 2007, 1:00 - 3:00 pm1 Apr 2007450: A Novel B2-Microglobulin/Protein Kinase A/Vascular Endothelial Growth Factor Signaling Axis Promotes Human Renal Cell Carcinoma Growth and Bone Metastasis Takeo Nomura, Wen-Chin Huang, Daqing Wu, Hiromitsu Mimata, Fray F. Marshall, Haiyen E. Zhau, Majd Zayzafoon, M. Neale Weitzmann, and Leland W.K. Chung Takeo NomuraTakeo Nomura More articles by this author , Wen-Chin HuangWen-Chin Huang More articles by this author , Daqing WuDaqing Wu More articles by this author , Hiromitsu MimataHiromitsu Mimata More articles by this author , Fray F. MarshallFray F. Marshall More articles by this author , Haiyen E. ZhauHaiyen E. Zhau More articles by this author , Majd ZayzafoonMajd Zayzafoon More articles by this author , M. Neale WeitzmannM. Neale Weitzmann More articles by this author , and Leland W.K. ChungLeland W.K. Chung More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)30703-1AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "450: A Novel B2-Microglobulin/Protein Kinase A/Vascular Endothelial Growth Factor Signaling Axis Promotes Human Renal Cell Carcinoma Growth and Bone Metastasis." The Journal of Urology, 177(4S), p. 151 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 151 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Takeo Nomura More articles by this author Wen-Chin Huang More articles by this author Daqing Wu More articles by this author Hiromitsu Mimata More articles by this author Fray F. Marshall More articles by this author Haiyen E. Zhau More articles by this author Majd Zayzafoon More articles by this author M. Neale Weitzmann More articles by this author Leland W.K. Chung More articles by this author Expand All Advertisement PDF DownloadLoading ...

Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members

The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Delta11/Delta11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging.

Steroid hormones, polypeptide growth factors, hormone refractory prostate cancer, and the neuroendocrine phenotype.

The growth, development, and differentiation of the prostate gland is largely dependent on the action of androgens and peptide growth factors that act differentially at the level of the mesenchymal and epithelial compartments. It is our premise that to understand the emergence of metastatic and hormone refractory prostate cancer we need to investigate: (1) how androgen action at the level of the mesenchyme induces the production of peptide growth factors that in turn can facilitate the growth and development of the epithelial compartment; (2) how androgen action at the level of the epithelium induces and maintains cellular differentiation, function, and replicative senescence; and (3) how transformation of the prostate gland can corrupt androgen and growth factor signaling homeostasis. To this end, we focus our discussion on how deregulation of the growth factor signaling axis can cooperate with deregulation of the androgen signaling axis to facilitate transformation, metastasis, and the emergence of the hormone refractory and neuroendocrine phenotypes associated with progressive androgen-independent prostate cancer. Finally, we suggest a working hypothesis to explain why hormone ablation therapy works to control early disease but fails to control, and may even facilitate, advanced prostate cancer.