Transforming growth factor-β and the hallmarks of cancer

Tumorigenesis is in many respects a process of dysregulated cellular evolution that drives malignant cells to acquire six phenotypic hallmarks of cancer, including their ability to proliferate and replicate autonomously, to resist cytostatic and apoptotic signals, and to induce tissue invasion, metastasis, and angiogenesis. Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that functions as a formidable barrier to the development of cancer hallmarks in normal cells and tissues. Paradoxically, tumorigenesis counteracts the tumor suppressing activities of TGF-β, thus enabling TGF-β to stimulate cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant cells overcome the cytostatic actions of TGF-β, and of how TGF-β stimulates the acquisition of cancer hallmarks by developing and progressing human cancers. Here we review the molecular and cellular mechanisms that underlie the ability of TGF-β to mediate tumor suppression in normal cells, and conversely, to facilitate cancer progression and disease dissemination in malignant cells.     

Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects

Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification, commonly referred to as “hardening of the arteries”. Because TGF-β can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be “atheroprotective”. The present review attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate the role of TGF-β in the many component pathways involved in atherogenesis.     

Beyond translation: elongation factor-1α and the cytoskeleton

Summary While reported interactions of elongation factor-1 (EF-1) with various other molecules involved in protein biosynthesis are abundant, its interactions with major cytoskeletal proteins have not been as extensively examined. Major roles for EF-1 in cytoskeletal organization emerge from a review of such interactions within species as diverse as slime molds and mammals, sea urchins and higher plants. Based on these studies, the integration of EF-1's cytoskeletal roles with those of translation is considered, and prospective mechanisms for regulation of EF-1's cytoskeletal associations are discussed.Abbreviations EF elongation factor - RNP ribonucleoprotein particle - MT microtubule - MA mitotic apparatus - CaM calmodulin - MAP microtubule-associated protein     

Inhibin and activin modulate transforming growth factor-β-induced immunosuppression

Inhibin, activin, and transforming growth factor (TGF) inhibited lipopoly-saccharide (LPS)-induced lymphocyte proliferation in a dose-dependent fashion. These induced suppressions were neutralized by coincubation of a preparation of antibodies to inhibin and TGF, respectively. Inhibin and activin also facilitated TGF-mediated immunosuppression of LPS-induced proliferation of splenocytes. These gonadal proteins showed no effect on phytohemagglutinin-or concanavalin A (Con-A)-induced proliferation of lymphocytes. However, inhibin facilitated and activin inhibited the TGF-mediated immunosuppression in thymocytes stimulated by Con-A. These findings suggest that inhibin or activin by itself, and/or together with TGF, may play an important role in immune response.     

Chronic hypoxia- and monocrotaline-induced elevation of hypoxia-inducible factor-1α levels and pulmonary hypertension

A close relationship exists between hypoxia-inducible factor (HIF)-1 and pulmonary hypertension. The present study was carried out to explore if there are temporal alterations in HIF-1 levels during prolonged hypoxia and after monocrotaline (MCT) treatment. First, young Wistar rats were divided into 5 groups: control, hypoxia-1, hypoxia-2, hypoxia-3 and hypoxia-4. Hypoxic rats were placed in a closed hypobaric chamber (380 mm Hg) for a 1-week (hypoxia-1), 2-week (hypoxia-2), 3-week (hypoxia-3) or 5-week (hypoxia-4) period. Second, other young Wistar rats were divided into 4 groups: control, MCT-1, MCT-2 and MCT-3. MCT-treated rats were injected subcutaneously once with MCT (60 mg/kg) for a 1-week (MCT-1), 2-week (MCT-2) or 3-week (MCT-3) period. Subsequently, pulmonary arterial pressure (Ppa) and the weight ratio of the right ventricle to the left ventricle plus the septum [RV/(LV + S)] were measured, and lungs were obtained for the determination of HIF-1 via Western blot analysis. Both hypoxia and MCT induced temporal increases in the Ppa, the ratio RV/(LV + S) and HIF-1 levels. A close relationship between the Ppa and HIF-1 level was found in both hypoxia- and MCT-treated animals. In addition, the PaO₂ level significantly decreased in rats 1–3 weeks after MCT treatment. These results, along with previous data in the literature, suggest that both chronic hypoxia- and MCT-induced lung hypoxia activate an increase in the production of HIF-1, and result in vascular remodeling and pulmonary hypertension.     

Transforming growth factor-β receptors: Role in physiology and disease

Transforming growth factor- (TGF-) plays a pivotal role in numerous vital cellular activities, most significantly the regulation of cellular proliferation and differentiation and synthesis of extracellular matrix components. Its ubiquitous presence in different tissues and strict conservation of nucleotide sequence down through the most primitive vertebrate organisms underscore the essential nature of this family of molecules. The effects of TGF- are mediated by a family of dedicated receptors, the TGF- types I, II, and III receptors. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors or their cognate ligands. The coding sequence of the human type II receptor appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. There are now substantial data suggesting that TGF- type II receptor should be considered a tumor suppressor gene. High levels of mutation in the TGF- type II receptor gene have been observed in a wide variety of primarily epithelial malignancies, including colon, gastric, and hepatic cancer. It appears likely that mutation of the TGF- type II receptor gene represents a very critical step in the pathway of carcinogenesis.     

Aging,osteoarthritis and transforming growth factor-β signaling in cartilage

Osteoarthritis is a common malady of the musculoskeletal system affecting the articular cartilage. The increased frequency of osteoarthritis with aging indicates the complex etiology of this disease, which includes pathophysiology and joint stability including biomechanics. The balance between anabolic morphogens and growth factors and catabolic cytokines is at the crux of the problem of osteoarthritis. One such signal is transforming growth factor-β (TGF-β). The impaired TGF-β signaling has been identified as a culprit in old mice in a recent article in this journal. This commentary places this discovery in the context of anabolic and catabolic signals and articular cartilage homeostasis in the joint.     

Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease, is featured by significantly elevated levels of various proinflammatory cytokines. Among numerous proinflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α), plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression is regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in the future.     

Expression of transforming growth factor-α mRNA and peptide in rodent kidneys

The expression and function of transforming growth factor alpha (TGF-α) in the kidney are not fully characterised. There exists controversy concerning the detection of renal TGF-α mRNA and the localisation of its immunoreactivity. In attempts to clarify the detection and localisation issue, the present study aimed to detect TGF-α mRNA in neonate and adult rat kidneys, to examine the specificity of two commonly used anti-TGF-α antibodies and finally to localise renal TGF-α immunoreactivity using a specific antibody. TGF-α mRNA of around 4.8 kb was readily detected with a sensitive non-radioactive northern analysis, with a similar abundance in neonatal and adult rat kidneys. Renal TGF-α peptide of the 6-kDa mature form was identified by western blotting. By using various controls, including specimens from TGF-α knock out mice in comparison with wild-type mice, the present study has confirmed the specificity of a polyclonal anti-human recombinant TGF-α antibody. With this antibody, TGF-α immunoreactivity was localised to the proximal tubules in renal cortex. In addition, the present study has also demonstrated a non-specificity in localising TGF-α in rodent kidneys by the most commonly used monoclonal anti-human TGF-α C-terminal peptide antibody, which stained collecting ducts in renal cortex and medulla. Accepted: 8 April 1999     

Transforming growth factor-β signaling: Tumorigenesis and targeting for cancer therapy

Transforming growth factor (TGF)-β is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-β is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-β is a main inducer of epithelial–mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-β exerts most of its functions by acting on TβRI and TβRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κβ are involved in the non-Smad TGF-β pathway. TGF-β acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-β are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-β signaling in cancer, among them the special focus is on TβRII suppression.     

Expression of hypoxia-inducible factor-1α and vascular density in mammary adenomas and adenocarcinomas in bitches

Background

The study aimed at examining hypoxia-inducible factor (HIF)1α expression in adenocarcinomas and adenomas in bitches in regard to tumour malignancy grade, proliferation, apoptosis and vascularisation. Therefore, paraffin sections of 15 adenomas and 64 adenocarcinomas sampled from 79 dogs aged 6 to 16 years were analysed.

Results

A significantly higher HIF-1α expression was noted in adenocarcinomas in comparison to adenomas (P?<?0.0004). Moreover, HIF-1α expression in adenocarcinomas correlated positively with tumour malignancy grade (r?=?0.59, P?<?0.05), Ki-67 antigen expression (r?=?0.43; P?<?0.0005), TUNEL-positive cells (r?=?0.62, P?<?0001) and tumour vascularity measured by quantification of vessels characterized by the expression of von Willebrand Factor (r?=?0.57, P?<?0.05).

Conclusion

Results of this study indicate a similar biological role of HIF-1α in dogs and in humans, which may confirm suitability of the animal model in investigations on progression of tumours in humans.

     

The roles of transforming growth factor-β and Smad3 signaling in adipocyte differentiation and obesity

We aimed at elucidating the roles of transforming growth factor (TGF)-β and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-β/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-β on adipogenesis was evaluated in mouse embryonic fibroblasts (MEF) isolated both from WT controls and Smad3 KO mice by Oil red-O staining and gene expression analysis. Phenotypic analyses of high-fat diet (HFD)-induced obesity in Smad3 KO mice compared to WT controls were performed. TGF-β/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-β significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-β on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-β inhibited adipogenesis independent from the Wnt and β-catenin pathway. Smad3 KO mice were protected against HFD-induced insulin resistance. The size of adipocytes from Smad3 KO mice on the HFD was significantly smaller compared to the controls. In conclusion, the TGF-β/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance.