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Growth hormone-releasing hormone (GHRH) is a hormone, produced by the hypothalamus which stimulates the pituitary gland to produce GH. Somatostatin secreted by the cells of hypothalamus and also by the cells of stomach, intestine, and pancreas that inhibits GH production. When pituitary secretes GH into the bloodstream, it results in the production of IGF-1 in the liver. IGF-1 is the factor that actually causes the growth of bones and other tissues of the body. It also plays an important role in signalling the pituitary to reduce GH production.
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![(a) 2D [15N-1H] HSQC spectrum of purified full-length hIGFBP-2 (1.0 mM;...](profile/Varsha-Brahmkhatri-2/publication/274376679/figure/fig3/AS:323026580197396@1454026946514/a-2D-15N-1H-HSQC-spectrum-of-purified-full-length-hIGFBP-2-10mM-nondeuterated_Q320.jpg)
Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailabili...
Citations
... Moreover, they can induce apoptosis in an IGF-independent way. However, they can enhance tumour growth and progression when the IGFBP proteases levels are upregulated and/or when IGF-BPs reacted with ECM [27]. ...
Hepatocellular carcinoma (HCC) was accompanied by high incidence of morbidity and mortality worldwide. Apoptosis is a vital biological process playing a critical role in cancer. Besides, toll like receptors were reported to regulator the innate immune response against cancer development. Exopolysaccharides (EPSs) derived from marine bacteria were reported to have a potential biological importance. This work aimed to elucidate the antitumor effects of newly isolated EPSs against HepG2 cells. Moreover, their effects on some apoptotic markers and TLRs were followed. Isolated EPSs were tested for their cytotoxic effects in a previous study and the most promising; MSA1, E4, MGA2, SGA3, and NRC7 EPSs were subjected to molecular analysis to investigate their pro-apoptotic effects, in addition to their effects on TLR2 and TLR-9 using quantitative real time RT-PCR. And the most cytotoxic and pro-apoptotic EPS; MSA1 were subjected to antibody array analysis to investigate a panel of 43 apoptotic proteins. All isolated EPSs produced a positive role in regulating the apoptotic gene and increasing the TLRs expression in different manners. However, the most promising EPS was MSA1. It showed pro-apoptotic effects on gene and protein levels, besides its up-regulation of TLRs.
... For hypoxia means a pathological condition caused by a lack of oxygen in the blood or in adipose tissue, while ischemia is a condition caused by an inadequate blood flow [184]. Hypertrophy of white adipocytes damages the microcirculation, the vascular network of the entire organ adipose creating conditions of obstruction and constriction of capillaries with endothelial damage in the white and brown adipose tissue [185,186]. Furthermore, the progressive hypertrophy of white adipocytes and the expansion of the white adipose tissue make the same adipocytes more away from the vascular network, with reduction of the volumes of oxygen available [187]. The adipose organ is a major consumer of oxygen and the condition of hypoxia/ischemia generates a greater state of oxidative stress, able to direct the white adipocytes hypertrophic/hypoxic and towards the secretion of inflammatory proteins and brown adipocytes towards a situation of dysfunction [188,189]. ...
J Jo ou ur rn na al l o of f C Ca an nc ce er r 2016; 7(15): Abstract Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link.
... IGF-IR has been introduced as a causative factor in the progression of breast cancer, and various strategies have been developed for targeting IGF-IR. Some of these strategies such as anti-IGF- IR monoclonal antibodies have entered clinical trials for breast cancer therapy [28, 29]. Because of different advantages of scFvs over whole antibodies, scFvs have been offered as appropriate tools for targeting cancer biomarkers, and so far, several scFvs with antitumor activity against breast cancer have been developed [25, 30, 31]. ...
Insulin-like growth factor I receptor (IGF-IR) is expressed on breast cancer cells and involves in metastasis, survival, and proliferation. Currently, application of IGF-IR-targeting monoclonal antibodies (mAbs), alone or in combination with other drugs, is a promising strategy for breast cancer therapy. Single-chain fragment variable (scFv) antibodies have been introduced as appropriate tools for tumor-targeting purposes because of their advantages over whole antibodies. In the present study, we employed a naïve phage library and isolated scFvs against a specific epitope from extracellular domain of IGF-IR by panning process. The selected scFvs were further characterized using polyclonal and monoclonal phage ELISA, soluble monoclonal ELISA, and colony PCR and sequencing. Antiproliferative and apoptotic effects of selected scFv antibodies on breast cancer cell lines were also evaluated by MTT and Annexin V/PI assays. The results of ELISA indicated specific reactions of the isolated scFvs against the IGF-IR peptide, and analyses of PCR product and sequencing confirmed the presence of full length VH and Vκ inserts. Treatment of MCF7 and SKBR3 cells with anti-IGF-IR scFv led to a significant growth inhibition. The results also showed that scFv treatment significantly augmented trastuzumab growth inhibitory effects on SKBR3 cells. The percentage of the apoptotic MCF7 and SKBR3 cells after 24-h treatment with scFv was 39 and 30.70 %, respectively. Twenty-four-hour treatment with scFv in combination with trastuzumab resulted in 44.75 % apoptosis of SKBR3 cells. Taken together, our results demonstrate that the targeting of IGF-IR by scFv can be an effective strategy in the treatment of breast cancer and provide further evidence for effectiveness of dual targeting of HER2 and IGF-IR in breast cancer therapy.
... Six different IGFBPs were characterized, but about 75 % of serum IGFs are bound to IGFBP3 and only 1 % of serum IGF-1 is free-bioactive form [24]. IGFBPs are also mostly synthesized in the liver. Nevertheless IGFs and IGFBPs are also produced in other organs, acting locally in autocrine and paracrine manner and mediating stromal -epithelial cell interactions [25]. IGFBPs acts in a competing manner against IGFR (IGF receptors) and IGFBP proteases. ...
Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.
... Mechanisms controlling cell proliferation are dependent of a complex cascade of events that, when altered or disrupted, can lead to a substantial increase in the risk of carcinogenesis. The growth hormone (GH) and insulin-like growth factor (IGF) system, which consists of GH, GH receptor (GHR), two growth factors (IGF-I and IGF-II), two cell surface receptors (IGF- IR and IGF-IIR), six binding proteins (IGFBPs) and a group of proteases, have a central role in the regulation of body growth and metabolic processes [1][2][3][4][5]. ...
... The final effect of these opposed forces in a tissue-specific environment is critical for normal and abnormal cell growth [1][2][3][4][5]. The association between GH and IGF system with carcinogenesis has long been postulated based on experimental, epidemiological and clinical data. ...
... IGF-I is also produced in several other tissues in response to GH and exerts a negative feedback effect on GH secretion by stimulation of somatostatin release in the hypothalamus and inhibition of GH gene transcription in the pituitary. The IGFBPs comprise a superfamily of six proteins (IGFBP-1 to -6) that bind to IGFs with high affinity and specificity and a family of IGFBPrelated proteins (IGFBP-rPs), which are structurally similar to the IGFBPs but bind IGFs with much lower affinity [5]. In plasma, most IGFs are associated with a high molecular weight complex (a ternary complex) consisting of IGFBP-3 and the acid labile subunit (ALS). ...
The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signaling pathways for cell growth that compete with other signaling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of GH-IGF system with carcinogenesis has long been hypothesized mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of GH-IGF system in tumor promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency or treated with GH is much weaker. In this review, we will attempt to consolidate this data.
... With the large body of preclinical proof that the IGF-I/IGF-IR axis plays a pivotal role in the pathogenesis of MM, interest in this axis as a potential therapeutic target has grown. Several strategies to specifically target the IGF-IR have been developed and tested for their antimyeloma activity in preclinical myeloma models and clinical trials [80, 156]. ...
Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.
... The rIGFBP7 product, as an active protein, displayed inhibitory effects on rIGF-1-induced cell proliferation. These data are consistent with the observations by Evdokimova et al. [37], indicating the potential of rIGFBP7 as a novel IGF-1-targeted therapy [38]. Further animal experiments should to be performed to confirm anti-tumor activity of rhIGFBP7 in vivo in future. ...
Urine provides an ideal source for disease biomarker discovery. High-adhesion contaminants such as urobilin, which are difficult to remove from urine, can severely interfere with urinary proteomic analysis. Here, we aimed to establish a strategy based on single-pot, solid-phase-enhanced sample preparation (SP3) technology to prepare samples for urinary proteomics analysis that almost completely eliminates the impact of urobilin. A systematic evaluation of the effects of two urinary protein precipitation methods, two types of protein lysis buffers, and different ratios of magnetic digestion beads on the identification and quantification of the microscale urinary proteome was conducted. Our results indicate that methanol-chloroform precipitation, coupled with efficient lysis facilitated by urea, and subsequent enzymatic digestion using a mix of hydrophilic and hydrophobic magnetic beads offers the best performance. Further applying this strategy to the urine of patients with benign prostatic hyperplasia, prostate cancer and healthy individuals, combined with a narrow window of data-independent acquisition, FGFR4, MYLK, ORM2, GOLM1, SPP1, CD55, CSF1, DLD and TIMP3 were identified as potential biomarkers to discriminate benign prostatic hyperplasia and prostate cancer patients.
Pregnancy associated plasma protein-A (PAPP-A) plays an integral role in breast cancer (BC), especially triple negative breast cancer (TNBC). This subtype accounts for the most aggressive BC, possesses high tumor heterogeneity, is least responsive to standard treatments and has the poorest clinical outcomes. There is a critical need to address the lack of effective targeted therapeutic options available. PAPP-A is a protein that is highly elevated during pregnancy. Frequently, higher PAPP-A expression is detected in tumors than in healthy tissues. The increase in expression coincides with increased rates of aggressive cancers. In BC, PAPP-A has been demonstrated to play a role in tumor initiation, progression, metastasis including epithelial-mesenchymal transition (EMT), as well as acting as a biomarker for predicting patient outcomes. In this review, we present the role of PAPP-A, with specific focus on TNBC. The structure and function of PAPP-A, belonging to the pappalysin subfamily, and its proteolytic activity are assessed. We highlight the link of BC and PAPP-A with respect to the IGFBP/IGF axis, EMT, the window of susceptibility and the impact of pregnancy. Importantly, the relevance of PAPP-A as a TNBC clinical marker is reviewed and its influence on immune-related pathways are explored. The relationship and mechanisms involving PAPP-A reveal the potential for more treatment options that can lead to successful immunotherapeutic targets and the ability to assist with better predicting clinical outcomes in TNBC.
Simple Summary
The rise in worldwide uterine cancer is tied to increasing obesity, influencing substances such as adipocytokines and insulin-like growth factors (IGFs) in the body, promoting cancer mainly through inflammation. Our main objective was to evaluate the levels of adiponectin, leptin, TNFα, IL6, IGFs 1 and 2 in endometrial cancer patients compared to control patients and to examine their relationship with obesity. Additionally, we aimed to explore the correlation between these markers and tumour characteristics. We also conducted a reassessment of the markers 6 months post-surgery to investigate the impact of treatment on these markers. Given the absence of established biomarkers for endometrial cancer, studying these markers and their variations post-surgery may provide valuable prognostic insights.
Abstract
The rising global incidence of uterine cancer is linked to the escalating prevalence of obesity. Obesity results in alterations in adipocytokines and IGFs, driving cancer progression via inflammation, increased cell proliferation, and apoptosis inhibition, although the precise mechanisms are still unclear. This study examined a set of six markers, namely, adiponectin, leptin, IL6, TNFα, IGF1, and IGF2 and compared them between fifty age-matched endometrial cancer patients (study group) and non-cancer patients with benign gynaecological conditions (control group). We also assessed the relationship of these markers with obesity and explored the correlation between these markers and various tumour characteristics. In the cancer population, these markers were also assessed 24 h and 6 months post-surgery. Remarkably, low adiponectin levels were associated with a 35.8% increase in endometrial cancer risk. Interestingly, compared to control subjects where IGF levels decreased after menopause, post-menopausal women in the study group showed elevated IGF1 and IGF2 levels, suggesting a potential influence of endometrial cancer on the IGF system, particularly after menopause. Lastly, it is noteworthy that a discernible inverse relationship trend was observed in the levels of adipocytokines and IGFs 6 months post-surgery. This indicates that treatment for endometrial cancer may have a differential impact on adipocytokines and IGFs, potentially holding clinical significance that merits further investigation.
