Antibody targeting of TGF-β in cancer patients

The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-β's inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.     

The footprint of TGF-β in airway remodeling of the mustard lung

Abstract

Mustard lung is a major pulmonary complication in individuals exposed to sulfur mustard (SM) gas during the Iran–Iraq war. It shares common pathological and clinical features with some chronic inflammatory lung disorders, particularly chronic obstructive pulmonary disease (COPD). Airway remodeling, which is one of the main causes of lung dysfunction and the dominant phenomenon of chronic pulmonary diseases, is seen in the mustard lung. Among all mediators involved in the remodeling process, the transforming growth factor (TGF)-β plays a pivotal role in lung fibrosis and consequently in the airway remodeling. Regarding the high levels of this mediator detected in mustard lung patients, in the present study, we have discussed the possible roles of TGF-β in airway remodeling (including epithelial layer damage, subepithelial fibrosis and angiogenesis). Finally, based on TGF-β targeting, we have reviewed new airway remodeling therapeutic approaches.     

Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms

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Highlights► The renin angiotensin system plays a critical role on aortic aneurysmal formation and development. ► Angiotensin II and TGF-β have potential interactions in the development of aortic aneurysms. ► The definitive roles of TGF-β in the development of aortic aneurysms need to be clarified.     

Therapeutic strategies to target TGF-β in the treatment of bone metastases

Bone is one of the most common organs to be affected in patients with metastatic cancer. These bone metastases are often accompanied by bone destruction, bone fractures, pain, and hypercalcemia. Transforming growth factor-β (TGF-β) is a major bone-derived factor that is released in active form upon osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between tumor cells and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. In this review, preclinical and clinical data are evaluated for the potential use of TGF-β inhibitors in clinical practice to treat bone metastases.     

TGF-β signalling and immunity in prostate tumourigenesis

Importance of the field: The TGF-β's are pleiotropic cytokines that regulate multiple cellular functions. Their role in the prostate is important for normal prostate development and also in prostate tumourigenesis.

Areas covered in this review: The interactions TGF-β-mediated signalling has with maintaining prostate health, as well as its role in prostate tumourigenesis and prostate tumour immune evasion, with emphasis on how a breakdown in these interactions may influence disease progression.

What the reader will gain: That TGF-β influences normal prostate growth and differentiation by regulating the balance between epithelial cell proliferation and apoptosis, and involving the androgen receptor pathway. That TGF-β protects and maintains prostate stem cells and a review of the contrasting role TGF-β has in prostate tumourigenesis and tumour development, where TGF-β acts as a tumour suppressor and then switches roles to become a tumour promoter, and creates a local immunosuppressive niche leading to systemic tumour tolerance.

Take home message: TGF-β signalling in prostate cancer is a valid target for the treatment of this disease; however any therapeutic regimen will require an understanding of all aspects of the TGF-β-signalling nexus, otherwise by the very pleiotrophic nature of TGF-β, limited clinical benefits may result.     

Development of TGF-β resistance during malignant progression

Transforming growth factor-beta (TGF-beta) is the prototypical multifunctional cytokine, participating in the regulation of vital cellular activities such as proliferation and differentiation as well as a number of basic physiological functions. The effects of TGF-beta are critically dependent on the expression and distribution of a family of TGF-beta receptors, the TGF-beta types I, II, and III. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors. The coding sequence of the type II receptor (RII) appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. By virtue of its key role in the regulation of cell proliferation, TGF-beta RII should be considered as a tumor suppressor gene. High levels of mutation in the TGF-beta RII gene have been observed in a wide range of primarily epithelial malignancies, including colon and gastric cancer. It appears likely that mutation of the TGF-beta RII gene may be a very critical step in the pathway of carcinogenesis.     

TGF-β inhibitors for the treatment of cancer

Advances in understanding the role of transforming growth factor (TGF)-β in tumorigenesis have led to the development of TGF-β inhibitors for cancer treatment. Three platforms of TGF-β inhibitors have evolved: antisense oligonucleotides, monoclonal antibodies and small molecules. In this review, the current stage of development of each known TGF-β inhibitor will be discussed. As part of the risk/benefit assessment of TGF-β inhibitors, the known effects of TGF-β deficiency in mice, non-clinical toxicology studies with TGF-β inhibitors in rats, and the clinical studies with monoclonal antibodies against TGF-β will be summarised.     

TGF-β and calcitriol

Vitamin D₃ and transforming growth factor-β (TGF-β) are molecules from unrelated families that share identical actions on cell growth and differentiation. The active metabolite of vitamin D₃, calcitriol (1α,25-dihydroxyvitamin D₃), induces an inhibitory effect on the growth of various cell types, and the expression of different markers of cell differentiation. As the receptor of vitamin D₃ is ubiquitous, these effects are widespread in the organism. TGF-β is a growth factor produced by many cell types, and is a known inhibitor of the proliferation of epithelial cells. Because of the similarity in their actions, many studies have been aimed at defining some interactions between the two substances. The purpose of this article is to illustrate the nature of the interactions, and two examples are developed. In normal or transformed epithelial cells, it has been demonstrated that the inhibitory effect of calcitriol on cell growth could be related to an induction of TGF-β synthesis, and of a paracrine/autocrine loop. In bone, where both compounds play a very important role on the mechanisms controlling bone formation and remodeling, the interplay is more complex, and even includes the receptors of the two substances. Interest in this topic is growing and will surely lead to the establishment of new links between those two compounds.     

Involvement of neuronal TGF-β activated kinase 1 in the development of tolerance to morphine-inducedantinociception in rat spinal cord

Background and Purpose

Tolerance induced by morphine and other opiates remains a major unresolved problem in the clinical management of pain. There is now good evidence for the importance of MAPKs in morphine-induced antinociceptive tolerance. A member of the MAPK kinase kinase family, TGF-β activated kinase 1 (TAK1) is the common upstream kinase of MAPKs. Here, we have assessed the involvement of TAK1 in the development of tolerance to morphine-induced analgesia.

Experimental Approach

The effects of an antagonist of TAK1 on morphine tolerance were investigated in vivo using the Randall–Selitto test, and the mechanism was investigated using Western blot and immunohistochemistry. The expression of TAK1 after chronic morphine exposure was also evaluated in vitro by immunohistochemistry.

Key Results

Chronic intrathecal morphine exposure up-regulated protein levels and phosphorylation of spinal TAK1. TAK1 immunoreactivity was co-localized with the neuronal marker NeuN. Intrathecal administration of 5Z-7-oxozeaenol (OZ), a selective TAK1 inhibitor, attenuated the loss of morphine analgesic potency and morphine-induced TAK1 up-regulation. Furthermore, OZ decreased the up-regulated expression of spinal p38 and JNK after repeated morphine exposure. In vitro studies demonstrated that sustained morphine treatment induced TAK1 up-regulation, which was reversed by co-administration of OZ. A bolus injection of OZ showed some reversal of established morphine antinociceptive tolerance.

Conclusions and Implications

TAK1 played a pivotal role in the development of morphine-induced antinociceptive tolerance. Modulation of TAK1 activation by the selective inhibitor OZ in the lumbar spinal cord may prove to be an attractive adjuvant therapy to attenuate such tolerance.     

Expression and Significance of IL-6, IL-17 and TGF-β in Cystitis Glandularis

目的:探讨白细胞介素(IL)-6、IL-17和转化生长因子(TGF)-β在腺性膀胱炎(CG)组织中的表达及其在CG发病及进展中的作用.方法:将15例正常膀胱黏膜定为对照(A)组,43例未复发CG定为治愈(B)组,13例复发和癌变的CG定为进展(C)组;检测3组IL-6、IL-17和TGF-β的表达情况,并分析这些因子与CG发病及进展的相关性.结果:A组、B组及C组IL-6、IL-17和TGF-β的阳性表达率差异均有统计学意义(P＜0.01).3种因子与CG发病(rs分别为0.431、0.545、0.354,P＜0.05)和进展(rs分别为0.426、0.333、0.288,P＜0.05)呈正相关;IL-17分别与IL-6、TGF-β呈正相关(rs分别为0.997、0.961,P＜0.05).结论:IL-6、IL-17和TGF-3可能在CG的发病及进展中起重要作用.     

Role of PKC-β in chemical allergen-induced CD86 expression and IL-8 release in THP-1 cells

We previously demonstrated an age-related decrease in receptor for activated C-kinase (RACK-1) expression and functional deficit in Langerhans cells’ responsiveness. This defect specifically involves the translocation of protein kinase C (PKC)-β. The purpose of this study was to investigate the role of RACK-1 and PKC-β in chemical allergen-induced CD86 expression and IL-8 release in the human promyelocytic cell line THP-1 and primary human dendritic cells (DC). Dinitrochlorobenzene, p-phenylenediamine and diethyl maleate were used as contact allergens. The selective cell-permeable inhibitor of PKC-β and the broad PKC inhibitor GF109203X completely prevented chemical allergen- or lipopolysaccharide (LPS)-induced CD86 expression and significantly modulated IL-8 release (50 % reduction). The selective cell-permeable inhibitor of PKC-ε (also known to bind to RACK-1) failed to modulate allergen- or LPS-induced CD86 expression or allergen-induced IL-8 release, while modulating LPS-induced IL-8 release. The use of a RACK-1 pseudosubstrate, which directly activates PKC-β, resulted in dose-related increase in CD86 expression and IL-8 release. Similar results were obtained with human DC, confirming the relevance of results obtained in THP-1 cells. Overall, our findings demonstrate the role of PKC-β and RACK-1 in allergen-induced CD86 expression and IL-8 production, supporting a central role of PKC-β in the initiation of chemical allergen-induced DC activation.     

Role of transforming growth factor-β pathway in the mechanism of wound healing by saponin from Ginseng Radix rubra

1. The effects of saponin from Ginseng Radix rubra on extracellular matrix metabolism, the activation and synthesis of TGF-β1, and the modification of TGF-β receptor in fibroblasts were examined to elucidate the contribution of the TGF-β pathway to the mechanism of wound healing by saponin.
2. Fibronectin synthesis was analysed by the immunoprecipitation method. Activation and synthesis of TGF-β1 were measured by ELISA. The expressions of TGF-β receptors in fibroblasts were examined at protein and mRNA levels by the cross-linking method and Northern blot analysis, respectively.
3. The fibronectin synthesis increased 2.3- and 3.9-fold at fibroblasts treated with 1 and 10 μg ml⁻¹ of saponin, respectively, compared with that in non-treated cells. Fibronectin synthesis stimulated with 10 μg ml⁻¹ of saponin was inhibited with 69% by 5 μg ml⁻¹ of an anti-TGF-β1 antibody. mRNA of TGF-β type I receptor increased 4.8- and 4.4-fold at fibroblasts treated with 1 and 10 μg ml⁻¹ of saponin, respectively, and that of TGF-β type II receptor also increased 3.4- and 3.2-fold at fibroblasts treated with 1 and 10 μg ml⁻¹ of saponin, respectively. The significant increases of TGF-β type I and II receptors and of fibronectin synthesis were observed at the same concentrations of saponin. TGF-β1 content increased 1.74- and 1.87-fold at conditioned medium of fibroblasts treated with 100 and 250 μg ml⁻¹ of saponin, respectively, higher concentrations than those which accelerated fibronectin synthesis. Furthermore, the active TGF-β1 content was below 10% of total TGF-β1 at each concentration of saponin.
4. These results indicate that saponin stimulates fibronectin synthesis through the changes of TGF-β receptor expressions in fibroblasts.

     

Role of TGF-β/Smad signaling pathway in pulmonary fibrosis after rheumatoid arthritis in mice北大核心CSCD

Aim To investigate the role of TGF-β/Smad signaling pathway in rheumatoid arthritis (RA) - associated postinterstitial pulmonary fibrosis in mice. Methods The mouse model of RA was constructed by subcutaneous administration of complete Freund's adjuvant (CFA) and chicken II collagen (Col-II) to the tail root of mice. The blank group was given the same amount of distilled water, and the control group was given the same amount of glacial acetic acid (solvent). The degree of toe swelling (joint swelling degree and arthritis index) was monitored to evaluate the mouse modeling. The pathological changes of mouse lung tissues were observed by HE and Masson staining. The expression of TGF-β in lung tissues were observed by immunohistochemical staining. The level of hydroxyproline in lung tissues was measured by chemiluminescence method. The expressions of Smad2, Smad3 and phosphorylated p-Smad2 and phosphorylated p-Smad3 in lung tissues were detected by Western blot. Results Compared with blank group and solvent group, the joint swelling and arthritis index of model group significantly increased. Twenty-one days after administration, HE staining showed inflammatory changes in lung interstitium of the model group, Masson staining showed collagen fiber deposition and obvious fibrosis in lung interstitium of the model group, and immunohistochemical staining showed that the expression of TGF-β in cytoplasm of lung interstitial cells of the model group increased, which was brown and yellow. Meanwhile, hydroxyproline was significantly raised in lung tissue homogenate of the model group. Further WB analysis showed that compared with blank group and solvent group, the expression of p-Smad2 and pSmad3 in lung tissues of the model group was significantly up-regulated (P < 0. 05, P < 0. 01). Conclusions RA can give rise to pulmonary fibrosis, and the expressions of p-Smad2 and p-Smad3 are up-regulated, which is be pivotal in pulmonary fibrosis and RA-related post-interstitial pulmonary fibrosis. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by modulation in TGF-β expression

Dyslipidemia is common in patients with diabetes mellitus (DM) and is considered a risk factor for the progression of diabetic nephropathy (DN). Hyperlipidemia and hyperglycemia act synergistically to induce renal injury. The present study was designed to investigate the protective effects of tocotrienols as tocotrienol-rich fraction (TRF) extracted from palm (PO) and rice bran oils (RBO) against lipid induced nephropathy in type-2 diabetic rats and its probable molecular mechanism. Male Wistar rats (175–200 g) were divided into four groups. The first group served as diabetic control, while the second and third groups received PO-TRF and RBO-TRF, respectively by gavage over a period of sixteen weeks post-induction of diabetes. The fourth group comprised of age-matched rats that served as normal control. The effects of TRF on serum lipid profile, oxidative stress markers, expression of TGF-β, fibronectin and collagen type IV were analyzed in the kidney of diabetic rats. Treatment with PO-TRF and RBO-TRF significantly improved glycemic status, serum lipid profile and renal function in type-2 diabetic rats. In addition, TRF supplementation down-regulated the expression of TGF-β, fibronectin and collagen type IV in the kidney of diabetic rats. Transforming growth factor-β (TGF-β) plays a critical role in progression of DN, but its modulation by tocotrienols in DN remains unexplored. TRF ameliorated lipid induced nephropathy in type-2 diabetes by its hypoglycemic, hypolipidemic and antioxidant activities as well as by modulation of TGF-β to prevent increased expression of collagen type IV and fibrinogen. We finally propose a mechanism for the expression of molecular markers that are significant in the events leading to diabetic nephropathy and its modulation by tocotrienols/TRF.     

Strategies for TGF-β modulation: a review of recent patents

Background: TGF-β has been identified as a key factor in the progression of various diseases, in particular cancer and fibrosis. The signaling of TGF-β can be modulated through three distinct strategies: using antisense nucleotides that block TGF-β mRNA (trabedersen (AP 12009)), using monoclonal antibodies to block TGF-β isoforms (lerdelimumab, metelimumab) or using small molecule inhibitors of the TGF-β receptor 1 (TGF-βR1 or ALK-5). Objective: This review focuses on small molecules and summarizes the most recent TGF-βR1 inhibitors reported in the patent literature. Methods: We searched and analyzed the patent literature claiming chemical matter for TGF-βR1 inhibition from the 1^st of January 2005 to the 1^st of January 2009. Results/conclusions: The inhibition of TGF-β has recently been clinically validated with antisense nucleotide trabedersen. Small molecules inhibitors of TGF-βR1 that are now in Phase I clinical trials and in preclinical stage are, therefore, of high interest and could provide a more versatile route to TGF-β modulation through oral dosing while maintaining the same therapeutic benefits.     

The Role of β-Blockers in Melanoma

Journal of Neuroimmune Pharmacology - Melanoma is one of the most aggressive and less chemotherapy-responsive human cancers, representing a major public health issue worldwide. The early diagnosis...