scholarly journals Endoglin Targeting: Lessons Learned and Questions That Remain

2020 ◽  
Vol 22 (1) ◽  
pp. 147
Author(s):  
Yingmiao Liu ◽  
Madelon Paauwe ◽  
Andrew B. Nixon ◽  
Lukas J.A.C. Hawinkels
Keyword(s):  
Cancer Patients ◽  
Functional Role ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Lessons Learned ◽  
Poor Survival ◽  
Cancer Models ◽  
Preclinical Work ◽  
Combined Data

Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high expression on tumor vessels and its correlation with poor survival in cancer patients led to the exploration of endoglin as a therapeutic target for cancer. The endoglin neutralizing antibody TRC105 (Carotuximab®, Tracon Pharmaceuticals (San Diego, CA, USA) was subsequently tested in a wide variety of preclinical cancer models before being tested in phase I-III clinical studies in cancer patients as both a monotherapy and in combination with other chemotherapeutic and anti-angiogenic therapies. The combined data of these studies have revealed new insights into the role of endoglin in angiogenesis and its expression and functional role on other cells in the tumor microenvironment. In this review, we will summarize the preclinical work, clinical trials and biomarker studies of TRC105 and explore what these studies have enabled us to learn and what questions remain unanswered.

High Expression of sLex Associated with Poor Survival in Argentinian Colorectal Cancer Patients

2014 ◽  
Vol 29 (1) ◽  
pp. e30-e39 ◽  
Author(s):  
Ariel Zwenger ◽  
Martin Rabassa ◽  
Sandra Demichelis ◽  
Gabriel Grossman ◽  
Amada Segal-Eiras ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lymph Nodes ◽  
Cancer Patients ◽  
Normal Mucosa ◽  
Poor Survival ◽  
Primary Tumors ◽  
Metastatic Lymph Nodes ◽  
Metastatic Lymph ◽  
Colorectal Cancer Patients

Aim Colorectal cancer (CRC) is one of the most prevalent malignancies in Argentina with 11,043 new cases and 6,596 deaths estimated to have occurred in 2008. The present study was developed to clarify the differential expression of MUC1, MUC2, sLex, and sLea in colorectal cancer patients and their relationship with survival and clinical and histological features. Methods Ninety primary tumor samples and 43 metastatic lymph nodes from CRC patients were studied; follow-up was documented. Twenty-six adenoma and 68 histological normal mucosa specimens were analyzed. An immunohistochemical approach was applied and statistical analysis was performed. Results In tumor samples, MUC1, sLea, and sLex were highly expressed (94%, 67%, and 91%, respectively); also, we found a significantly increased expression of the 3 antigens in primary tumors and metastatic lymph nodes compared with normal mucosa and adenomas. MUC2 was expressed in 52% of both normal mucosa and CRC samples; this reactivity significantly decreased in metastatic lymph nodes (p<0.05). A multiple comparison analysis showed that MUC1 and sLex discriminated among 3 groups: normal, adenoma, and CRC tissues. The increase of sLex expression showed an association with recurrence, and survival analysis showed that a high sLex staining was significantly associated with a poor survival. By multivariate analysis MUC1 inmunoreactivity correlated positively and significantly with tumor size, while MUC2 expression showed the opposite correlation. Conclusions The correlation of sLex overexpression in primary tumors and metastatic lymph nodes, the discrimination among the normal, adenoma, and CRC groups based on sLex expression, as well as its association with recurrence and survival, all suggest a prognostic role of sLex in Argentinian CRC patients.

scholarly journals Role of TGF-alpha in the progression of diabetic kidney disease

2017 ◽  
Vol 312 (6) ◽  
pp. F951-F962 ◽  
Author(s):  
Josef G. Heuer ◽  
Shannon M. Harlan ◽  
Derek D. Yang ◽  
Dianna L. Jaqua ◽  
Jeffrey S. Boyles ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Neutralizing Antibodies ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Neutralizing Antibody ◽  
Diabetic Kidney

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal TGFA mRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx) db/db DKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.

scholarly journals Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1

2004 ◽  
Vol 165 (5) ◽  
pp. 723-734 ◽  
Author(s):  
Justin P. Annes ◽  
Yan Chen ◽  
John S. Munger ◽  
Daniel B. Rifkin
Keyword(s):  
Functional Role ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Basic Amino Acid ◽  
Potential Interaction ◽  
Specific Function ◽  
Integrin Αvβ6 ◽  
The Matrix ◽  
Hinge Domain

Transforming growth factor-βs (TGF-β) are secreted as inactive complexes containing the TGF-β, the TGF-β propeptide, also called the latency-associated protein (LAP), and the latent TGF-β binding protein (LTBP). Extracellular activation of this complex is a critical but incompletely understood step in TGF-β regulation. We have investigated the role of LTBP in modulating TGF-β generation by the integrin αVβ6. We show that even though αvβ6 recognizes an RGD on LAP, LTBP-1 is required for αVβ6-mediated latent TGF-β activation. The domains of LTBP-1 necessary for activation include the TGF-β propeptide-binding domain and a basic amino acid sequence (hinge domain) with ECM targeting properties. Our results demonstrate an LTBP-1 isoform-specific function in αVβ6-mediated latent TGF-β activation; LTBP-3 is unable to substitute for LTBP-1 in this assay. The results reveal a functional role for LTBP-1 in latent TGF-β activation and suggest that activation of specific latent complexes is regulated by distinct mechanisms that may be determined by the LTBP isoform and its potential interaction with the matrix.

scholarly journals Role of transforming growth factor-β1in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis

1996 ◽  
Vol 5 (1) ◽  
pp. 37-42 ◽  
Author(s):  
Irma Lemaire ◽  
Sophie Ouellet
Keyword(s):  
Growth Factor ◽  
Alveolar Macrophages ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Significant Inhibition ◽  
Prostaglandin E ◽  
Tumour Necrosis Factor Production

Activation of alveolar macrophages (AM) for tumour necrosis factor production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF suppression, notably the role of other AM-derived mediators including prostaglandin E2(PGE2), transforming growth factor-β1(TGF-β1), and interleukin 6 (IL-6). The action of PGE2and TGF-β1, on AM was different. At physiologically relevant doses (25–300 pg/ml), PGE2did not cause significant inhibition of Hpopolysaccharide (Lps)-induced TNF release by AMin vitrobut stimulated IL-6 (up to six fold), an inhibitor of AM-derived TNT. In contrast, TGF-β1(0.5–50 ng/ml) inhibited both LPS-induced TNT and IL-6 release by 50% but had no effect on PGE2production by AM. To determine the respective contribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for weeks were treated with neutralizing antibody against TGF-β1or indomethacin, an inhibitor of PGE2synthesis. Treatment of rat AM with anti-TGF-β1but not indomethacin, abrogated the observed TNT suppression. These results suggest that an autocrine, TGF-β1-dependent mechanism is involved in the down-regulation of TNF production by rat AM from animals with lung fibrosis.

Functional role of transforming growth factor-β type III receptor during palatal fusion

2007 ◽  
Vol 236 (3) ◽  
pp. 791-801 ◽  
Author(s):  
Akira Nakajima ◽  
Yoshihiro Ito ◽  
Masatake Asano ◽  
Masao Maeno ◽  
Koichi Iwata ◽  
...  
Keyword(s):  
Growth Factor ◽  
Functional Role ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type Iii ◽  
Palatal Fusion

scholarly journals Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

2021 ◽  
Vol 11 (12) ◽  
pp. 1624
Author(s):  
Carolyn W. Harley ◽  
Qi Yuan
Keyword(s):  
Locus Coeruleus ◽  
Functional Role ◽  
Temporal Patterns ◽  
Lessons Learned ◽  
Behavioral State ◽  
Target Structure ◽  
Activation Patterns ◽  
Firing Patterns ◽  
Firing Rates

After reviewing seminal studies using optogenetics to interrogate the functional role of the locus coeruleus in behavior, we conclude that differences in firing rates and firing patterns of locus coeruleus neurons contribute to locus coeruleus nucleus heterogeneity by recruiting different output circuitry, and differentially modifying behavior. The outcomes initiated by different optogenetic input activation patterns and frequencies can have opposite consequences for behavior, activate different neurons in the same target structure, be supported by distinct adrenoceptors and vary with behavioral state.

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