Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer.

We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40-50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis.

The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy.

In recent years, the continuous optimization of anti-tumor therapy has greatly improved the cancer-specific survival rate for patients with breast cancer (BC). The prevention and treatment of breast cancer-related heart diseases have become a new breakthrough in improving the long-term survival for BC patient. The cardiac damages caused by BC treatment are increasingly prominent among BC patients, of which ischemic heart disease (IHD) is the most prominent. Besides, the systemic inflammatory response activated by tumor microenvironment c an induce and exacerbate IHD and increase the risk of myocardial infarction (MI). Conversely, IHD can also exert detrimental effects on tumors. MI not only increases the risk of BC, but also induces specialized immune cell to BC and accelerates the progression of BC. Meanwhile, the treatment of IHD can also promote BC metastasis and transition to more aggressive phenotypes. Although BC and IHD are diseases of two independent systems, their crosstalk increases the difficulty of anti-cancer treatment and IHD management, which reduces the survival for both diseases. Therefore, this review mainly explores the mutual influence and underlying mechanisms between BC and IHD, aiming to provide insights for improving the long-term survival for patients with BC or IHD.

Circadian Syndrome (CircS) is a significant marker of metabolic imbalance and has been linked to various chronic diseases. However, its relationship with cancer risk remains underexplored. This research aims to explore the relationship between CircS and cancer, while also assessing the possible mediating role of the triglyceride glucose (TyG) index.

Baseline data from the 2011 China Health and Retirement Longitudinal Study (CHARLS) and follow-up data from 2015 were analyzed, including participants' sociodemographic characteristics, health behaviors, and metabolic indicators. Linear regression, mediation analysis, and logistic regression were employed to explore relationships between CircS, cancer risk, and the TyG index, with a dose-response analysis conducted on TyG index and cancer risk.

Among 7,864 middle-aged and elderly participants, CircS was significantly and positively associated with cancer risk (r = 0.17, P < 0.001). The TyG index showed a significant correlation with both CircS (r = 0.52, P < 0.001) and cancer (r = 0.15, P < 0.001). Mediation modeling indicated that the TyG index partially mediated the association between CircS and cancer, accounting for 23% of this relationship. Additionally, a significant nonlinear dose-response relationship was observed between the TyG index and cancer risk (Pnonlinear = 0.0024).

Circadian syndrome is associated with increased cancer risk, with the TyG index partially mediating this relationship.

Using a nationwide population-based cohort, we primarily investigated whether overall and site-specific cancer risks are increased in patients with acromegaly.

The study included 2382 patients with acromegaly and 11 910 controls aged above 20, from 2006 to 2016. Cox hazards regression analysis was used, adjusting for baseline covariates. To investigate the association between acromegaly and cancer risk, we conducted Cox proportional hazards regression analysis with adjustments for age, sex, hypertension, diabetes, and dyslipidemia, and stratified the analysis by age (<50, 50-64, and ≥65 years), sex, and follow-up duration (<1, 1-4, and ≥5 years).

Among the 2382 patients with acromegaly, overall cancer occurred in 244 (10.2%), while the 11 910 controls had 707 (5.9%) occurrences (HR: 1.90 (95% confidence interval (CI): 1.63-2.22). Patients with acromegaly had the highest relative risk for brain cancers with an HR of 6.80 (95% CI: 2.83-16.38) and significantly higher risk of lymphoma, thyroid cancer, multiple myeloma, pancreatic cancer, and colorectal cancer. Even 5 years after the diagnosis of acromegaly, patients continued to show a significantly higher incidence of cancer. The overall cancer risk, particularly for stomach cancer, was significantly higher in patients under the age of 50 compared to older patients. No significant difference was observed between sexes.

This nationwide longitudinal cohort study shows an increased risk of cancer in patients with acromegaly Active and long-term cancer screening is necessary in patients with acromegaly.

Metformin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between metformin use and the risk of occurrence of prostate cancer (PCa). The purpose of this study was to assess the effect of metformin on clinical outcomes in patients with PCa in a meta-analysis and to explore the possible dose-response relationship.

A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of metformin on the risk of PCa. Relevant subgroup analyses and sensitivity analyses were performed.

The across studies results show that metformin use associated with lower incidence of PCa (RR: 0.82, 95% CI: 0.74-0.91). Metformin use was also found to reduce PCa recurrence, but the results were not statistically significant (RR: 0.97, 95% CI: 0.81-1.15). Metformin use was not associated with PCa mortality (RR: 0.94, 95% CI: 0.81-1.09). The results of subgroup analyses indicated that the type of study was a cohort study and the population came from both Asia and Europe showed that taking metformin reduced the incidence of PCa. A linear correlation was found between the duration of metformin use and its protective effect.

This meta-analysis revealed an independent correlation between metformin use and reduced incidence of PCa. Metformin use was not associated with either PCa recurrence rate or mortality. Furthermore, the effect of metformin on PCa incidence was found to be related to duration.

It is well known that aging affects many systems in the body. The digestive system is one of the systems most affected by aging. In our study, we examined the effects of young plasma treatment on cell proliferation, growth factors, immune defense and histological parameters in the jejunum of aged male rats. For this purpose, aged male Sprague Dawley rats (24 months, n = 7) were treated with pooled plasma (0.5 ml/day, intravenously for 30 days) collected from young (5 weeks, n = 51) rats. Aged rats that received young plasma treatment were grouped as the experimental group, while aged rats formed the control group. At the end of the experiment, the jejunums of the groups were collected and histological parameters such as villus height, crypt depth, total mucosal thickness and surface absorption areas were measured and compared. In addition, cell proliferation index and proliferation intensity in the crypt glands of the jejunum were evaluated with proliferating cell nuclear antigen and expressions of growth factors such as insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) expression and effects of immunoglobulin A (IgA), which plays a role in the defense of the digestive system against microorganisms, were examined. In the experimental group, an increase in histological parameters, IGF-R and IGF-IR expression, proliferation density, proliferation index and IgA expression density and IgA cell count were observed compared to the control group. These results suggest that young plasma treatment has a positive effect on the digestive system and may be a potential therapeutic for tissue regeneration.

Humans have limited capacity to regenerate lost tissues post injury. The ability to modulate regenerative repair of tissues offers possibilities for restoring loss of tissue (organ) structure and function. Zebrafish (Danio rerio) larvae fin fold regeneration model is a simple system to study the process of regeneration and associated cellular mechanisms. Berberine, a plant alkaloid which is known to have wound healing properties shows potential to modulate regeneration. The present study aimed to explore the modulating influence of berberine on the signaling pathways involved in zebrafish larvae transected tail fin fold regeneration. Tail fin fold transection was performed on 3 dpf (days post fertilization) zebrafish larvae treated with Berberine (0.01%) and untreated control (System water (SW)). The larvae were observed under a microscope at 0, 1, 2, 3, 4, 5, hours post transection (hpt). RNA was extracted from Berberine treated and untreated (control) tail fin transected larvae at 4 hpt to perform RNA-seq analysis. PPI (protein-protein interaction) network, Shiny GO functional enrichment and topology analysis of DEGs (differentially expressed genes) was performed. Berberine treated larvae showed an accelerated regeneration growth in their transected tail fin by 4 hpt. Berberine induced accelerated regeneration is associated with the involvement of Insulin, IGF, stress response, jak-stat, cytokine, and cellular reprogramming signaling pathways as per RNA-seq analysis and String PPI network, and Shiny GO functional enrichment analysis of DEGs. Topological analysis using Cytohubba revealed tnfa, stat3, jak2b, igf1, jak1, hsp90aa1.1, stat1a, stat1b, bag3, hsp70, and fosl1a as the key Hub genes in the PPI network. The present study identifies the pathways and the Hub proteins involved in berberine induced accelerated regeneration process in zebrafish larvae.

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho's role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho's multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses.

Technetium-99 m (99mTc) remains the cornerstone of nuclear medicine for single photon emission computed tomography (SPECT) due to its widespread availability and chemical and physical features. Its multiple oxidation states allow for the design and production of radiopharmaceuticals with versatile properties, namely in terms of pharmacokinetic profile. 99mTc(V) is the most common oxidation state, but 99mTc(I) gained traction after the pioneering work of Alberto and colleagues, which resulted in the introduction of the organometallic core fac-[99mTc(CO)3(H2O)3]+. This core is readily available from [99mTcO4]- and displays three labile water molecules that can be easily swapped for ligands with different denticity and/or donor atoms in aqueous environment. This makes it possible to radiolabel small molecules as well as high molecular weight molecules, such as antibodies or other proteins, while assuring biological activity. Direct radiolabelling of those proteins with fac-[99mTc(CO)3]+ under mild conditions is accomplished through incorporation of a polyhistidine tag (His-tag), a commonly used tag for purification of recombinant proteins. This review aims to address the direct radiolabelling of His-tagged macromolecules with fac-[99mTc(CO)3]+ for development of molecular imaging agents and the impact of this technology in the discovery and development of imaging and/or therapeutic agents towards clinical application.

We evaluate the predictive and prognostic value of insulin-like growth factor-I (IGF-1), IGF binding protein-2 (IGFBP-2) and -3 (IGFBP-3) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

This is a retrospective analysis of a multi-institutional database comprising 753 patients who underwent RNU for UTUC and had a preoperative plasma available. Logistic and Cox regression analyses were performed. The discriminative ability and clinical utility of the models was calculated using the lasso regression test, area under receiver operating characteristics curves, C-index, and decision curve analysis (DCA).

Lower preoperative plasma levels of IGFBP-2 and -3 independently correlated with increased risks of lymph node metastasis, pT3/4 disease, nonorgan confined disease, and worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) (all P ≤ .004). The addition of both IGFBP-2 and -3 to a postoperative multivariable model, that included standard clinicopathologic characteristics, improved the model's concordance index by 10%, 9%, and 8% for RFS, CSS, and OS, respectively. On DCA, addition of both IGFBP-2 and -3 to base models improved their performance for RFS, CSS, and OS by a statistically and clinically significant margin. Plasma IGF-1 was not associated with any of outcomes.

We confirmed that a lower plasma levels of IGFBP-2 and -3 both are independent and clinically significant predictors of adverse pathological features and survival outcomes in UTUC patients treated with RNU. These findings might help guide the clinical decision-making regarding perioperative systemic therapy and follow-up scheduling.

Peyronie's disease, a fibroinflammatory disorder, detrimentally impacts the sexual well-being of men and their partners. The manifestation of fibrotic plaques within penile tissue, attributed to dysregulated fibrogenesis, is pathognomonic for this condition. The onset of fibrosis hinges on the perturbation of the equilibrium between matrix metalloproteinases (MMPs), crucial enzymes governing the extracellular matrix, and tissue inhibitors of MMPs (TIMPs). In the context of Peyronie's disease, there is an elevation in TIMP levels coupled with a decline in MMP levels, culminating in fibrogenesis. Despite the scant molecular insights into fibrotic pathologies, particularly in the context of Peyronie's disease, a comprehensive literature search spanning 1995 to 2023, utilizing PubMed Library, was conducted to elucidate these mechanisms. The findings underscore the involvement of growth factors such as FGF and PDGF, and cytokines like IL-1 and IL-6, alongside PAI-1, PTX-3, HIF, and IgG4 in the fibrotic cascade. Given the tissue-specific modulation of fibrosis, comprehending the molecular underpinnings of penile fibrosis becomes imperative for the innovation of novel and efficacious therapies targeting Peyronie's disease. This review stands as a valuable resource for researchers and clinicians engaged in investigating the molecular basis of fibrotic diseases, offering guidance for advancements in understanding Peyronie's disease.

Alcohol consumption and hepatitis B virus (HBV) infection are common risk factors for hepatocellular carcinoma (HCC). However, few studies have focused on elucidating the mechanisms of HCC with combined alcohol and HBV etiology.

We aimed to investigate the molecular features of alcohol and HBV on HCC and to seek out potential therapeutic strategies.

Two independent cohorts of HCC patients (n = 539 and n = 140) were included to investigate HCC with synergetic alcohol and HBV (AB-HCC) background. Patient-derived cell lines, organoids, and xenografts were used to validate the metabolic fragile. High-throughput drug screening (1181 FDA-approved anticancer drugs) was leveraged to explore the potential therapeutic agents.

Here, we delineated AB-HCC as a distinctive metabolic subtype, hallmarked by oncogenic cholesterol, through the integration of clinical cohorts, proteomics, phosphoproteomics, and spatial transcriptome. Mechanistically, our findings revealed that cholesterol directly binds to CSNK2A1 (Casein Kinase 2 Alpha 1), augmenting its kinase activity and leading to phosphorylation of IGF2R (Insulin-Like Growth Factor 2 Receptor) at Ser2484. This cascade rewires lipid-driven mitochondrial oxidative phosphorylation, spawns reactive oxygen species measured by malondialdehyde assay, and perpetuates a positive feedback loop for cholesterol biosynthesis, ultimately culminating in tumorigenesis. Initial transcriptional activation of CSNK2A1 is driven by upregulation of RAD21 in AB-HCC. Our cholesterol profiling exposes AB-HCC's compensatory mechanism of AB-HCC, which capitalizes on both uptake and biosynthesis of cholesterol to confer survival edge. Moreover, high-throughput drug screening coupled with in vivo validation has uncovered the susceptibilities of AB-HCC, which can be effectively addressed by a combination of dietary cholesterol restriction and oral administration of Fostamatinib. The CSNK2A1-mediated cholesterol biosynthesis pathway has been implicated in various cancers characterized by cholesterol metabolism.

These findings not only pinpoint the oncogenic metabolite cholesterol as a hidden culprit in AB-HCC subtype, but also enlighten a novel combination strategy to rejuvenate tumor metabolism.

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the need for novel therapeutic strategies. Trophoblast cell surface antigen 2 (Trop-2), a type I transmembrane glycoprotein highly expressed in various solid tumors including all subtypes of breast cancer, has emerged as a promising target for cancer therapy. This review focuses on recent advancements in Trop-2-targeted antibody-drug conjugates (ADCs) for breast cancer treatment. We comprehensively analyzed the structure and mechanism of action of ADCs, as well as the role of Trop-2 in breast cancer progression and prognosis. Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. We systematically reviewed the ongoing clinical studies of these ADCs, highlighting their efficacy and safety profiles. Furthermore, we explored the potential of combining Trop-2-targeted ADCs with other therapeutic modalities, including immunotherapy, targeted therapies, and small molecule inhibitors. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients.

Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance. Considering the diversity of organs infiltrated by T-ALL cells and the unique cellular components of the microenvironment encountered at each site, it is likely that there are both shared features of tumor-supportive niches across multiple organs and site-specific features that are key to leukemia cell survival. Therefore, elucidating the distinct microenvironmental cues supporting T-ALL in different anatomic locations could reveal novel therapeutic targets to improve therapies. This review summarizes the current understanding of the intricate interplay between leukemia cells and the diverse cells they encounter within their tumor microenvironments (TMEs), as well as opportunities to therapeutically target the leukemic microenvironment.

The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1).

Male and female mice were used for our study. Age-related transcriptional changes were analyzed using quantitative PCR at three different time points: mature adult, middle-aged, and aged. Transcriptional changes during aging were further confirmed with digital droplet PCR. Additionally, we used immunohistochemical analysis (IHC) for the evaluation of in vivo protein expression. We further investigated the cellular phenotype of these NTFS, TJP, and water channel proteins in the mouse CP by co-labeling them with the classical vascular marker, Isolectin B4, and epithelial cell marker, Plectin.

Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJP's JAM, CLAUDIN1, CLAUDIN2 and CLAUDIN5 were reduced in aged mice.

Our study highlights transcriptional level changes in the CP during aging. The age-related transcriptional changes exhibit similarities as well as gene-specific differences in the CP of males and females. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.

Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms. Imatinib is the first-line therapy for GIST patients. Drug resistance limits the long-term effectiveness of imatinib. The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.

To further investigate the mechanism of IGF2 specific to GISTs.

IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data. After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays. We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins. We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.

Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance. GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT. Knockdown of IGF2 significantly inhibited those activities. In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice. IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis. GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance. Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs.

IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Insulin-like growth factor 1 (IGF-1), primarily synthesized in the liver, was initially discovered due to its capacity to replicate the metabolic effects of insulin. Subsequently, it emerged as a key regulator of the actions of growth hormone (GH), managing critical processes like cell proliferation, differentiation, and apoptosis. Notably, IGF-1 displays a longer half-life compared to GH, making it less susceptible to factors that may affect GH concentrations. Consequently, the measurement of IGF-1 proves to be more specific and sensitive when diagnosing conditions such as acromegaly or GH deficiency. The recognition of the existence of IGFBPs and their potential to interfere with IGF-1 immunoassays urged the implementation of various techniques to moderate this issue and provide accurate IGF-1 results. Additionally, in response to the limitations associated with IGF-1 immunoassays and the occurrence of discordant IGF-1 results, modern mass spectrometric methods were developed to facilitate the quantification of IGF-1 levels. Taking advantage of their ability to minimize the interference caused by IGF-1 variants, mass spectrometric methods offer the capacity to deliver robust, reliable, and accurate IGF-1 results, relying on the precision of mass measurements. This also enables the potential detection of pathogenic mutations through protein sequence analysis. However, despite the analytical challenges, the discordance in IGF-1 reference intervals can be attributed to a multitude of factors, potentially leading to distinct interpretations of results. The establishment of reference intervals for each assay is a demanding task, and it requires nationwide multicenter collaboration among laboratorians, clinicians, and assay manufacturers to achieve this common goal in a cost-effective and resource-efficient manner. In this comprehensive review, we examine the challenges associated with the standardization of IGF-1 measurement methods, the minimization of pre-analytical factors, and the harmonization of reference intervals. Particular emphasis will be placed on the development of IGF-1 measurement techniques using "top-down" or "bottom-up" mass spectrometric methods.

Inflammation is a risk factor for tumorigenesis. Macrophage, a subset of immune cells with high plasticity, plays a multifaceted role in this process. Natural products, which are bioactive compounds derived from traditional herbs or foods, have exhibited diverse effects on macrophages and tumorigenesis making them a valuable resource of drug discovery or optimization in tumor prevention.

Provide a comprehensive overview of the various roles of macrophages in tumorigenesis, as well as the effects of natural products on tumorigenesis by modulating macrophage function.

A thorough literature search spanning the past two decades was carried out using PubMed, Web of Science, Elsevier, and CNKI following the PRISMA guidelines. The search terms employed included "macrophage and tumorigenesis", "natural products, macrophages and tumorigenesis", "traditional Chinese medicine and tumorigenesis", "natural products and macrophage polarization", "macrophage and tumor related microenvironment", "macrophage and tumor signal pathway", "toxicity of natural products" and combinations thereof. Furthermore, certain articles are identified through the tracking of citations from other publications or by accessing the websites of relevant journals. Studies that meet the following criteria are excluded: (1) Articles not written in English or Chinese; (2) Full texts were not available; (3) Duplicate articles and irrelevant studies. The data collected was organized and summarized based on molecular mechanisms or compound structure.

This review elucidates the multifaceted effect of macrophages on tumorigenesis, encompassing process such as inflammation, angiogenesis, and tumor cell invasion by regulating metabolism, non-coding RNA, signal transduction and intercellular crosstalk. Natural products, including vitexin, ovatodiolide, ligustilide, and emodin, as well as herbal remedies, have demonstrated efficacy in modulating macrophage function, thereby attenuating tumorigenesis. These interventions mainly focus on mitigating the initial inflammatory response or modifying the inflammatory environment within the precancerous niche.

These mechanistic insights of macrophages in tumorigenesis offer valuable ideas for researchers. The identified natural products facilitate the selection of promising candidates for future cancer drug development.

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

Over years, there has been a widespread quest for effective dietary patterns and natural extracts to mitigate prostate cancer risk. However, despite numerous experimental studies conducted on various natural extracts, the evidence substantiating their efficacy remains largely insufficient. This dearth of compelling evidence presents a significant challenge in advocating for their widespread use as preventive measures against prostate cancer.

Our study endeavors to undertake a network meta-analysis to evaluate the influence of natural extracts on prostate cancer.

Researchers systematically searched through Embase, PubMed, Cochrane Library, and Web of Science databases until December 2023. The main focus was on assessing primary outcomes comprising prostate-specific antigen (PSA), insulin-like growth factor-binding protein-3 (IGFBP-3), insulin-like growth factor-1 (IGF-1). We conducted data analysis utilizing StataMP 15.0 software. Therapeutic effects were ranked based on the probability values derived from Surface Under the Cumulative Ranking curve (SUCRA). Additionally, cluster analysis was employed to assess the impacts of natural extracts on three distinct outcomes.

Following screening procedures, the 28 eligible studies were incorporated, the selected studies encompassed 1,566 prostate cancer patients and evaluated 16 different natural extract treatments. Specifically, 24 trials included PSA indicators, 10 included IGF-1 indicators, and 8 included IGFBP-3 indicators. The findings revealed that, based on the SUCRA values, the combined therapy of silybin with selenium (74%) appears to be the most effective approach for reducing serum PSA levels. Simultaneously, silybin alone (84.6%) stands out as the most promising option for decreasing serum IGF-1 levels. Lastly, concerning IGFBP-3, silybin alone (67.7%) emerges as the optimal choice. Twelve studies provided comprehensive information on adverse drug reactions/events (ADR/ADE), whereas five articles did not report any significant ADR/ADE.

The NMA suggests that, compared to placebo, utilizing silybin either alone or in combination with selenium has been shown to enhance therapeutic effects, offering potential benefits to patients with prostate cancer. This study can offer valuable insights for prostate patients considering natural extract treatments. Further evidence is required to confirm the safety profile of these treatments.

Tobacco smoking causes pulmonary inflammation, resulting in emphysema, an independent risk factor for lung cancer. Induction of insulin-like growth factor 2 (IGF2) in response to lung injury by tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and polycyclic aromatic hydrocarbon benzo[a]pyrene in combination (NB), is critical for the proliferation of alveolar type 2 cells (AT2s) for lung repair. However, persistent IGF2 overexpression during NB-induced severe injury results in hyperproliferation of AT2s without coordinated AT2-to-AT1 differentiation, disrupting alveolar repair, which leads to the concurrent development of emphysema and lung cancer. The current study aims to verify the role of IGF2 signaling in the associated development of emphysema and cancer and develop effective pharmaceuticals for the diseases using animal models that recapitulate the characteristics of these chronic diseases.

The pathogenesis of pulmonary emphysema and cancer was analyzed by lung function testing, histological evaluation, in situ zymography, dihydroethidium staining, and immunofluorescence and immunohistochemistry analyses utilizing mouse models of emphysema and cancer established by moderate exposure to NB for up to seven months.

Moderate NB exposure induced IGF2 expression in AT2s during the development of pulmonary emphysema and lung cancer in mice. Using AT2-specific insulin receptor knockout mice, we verified the causative role of sustained IGF2 signaling activation in AT2s in emphysema development. IGF2-targeting strategies, including voltage-dependent calcium channel blocker (CCB) and a neutralizing antibody, significantly suppressed the NB-induced development of emphysema and lung cancer. A publicly available database revealed an inverse correlation between the use of calcium channel blockers and a COPD diagnosis.

Our work confirms sustained IGF2 signaling activation in AT2s couples impaired lung repair to the concurrent development of emphysema and cancer in mice. Additionally, CCB and IGF2-specific neutralizing antibodies are effective pharmaceuticals for the two diseases.

Skeletal muscle (SKM), despite comprising ~40% of body mass, rarely manifests cancer. This review explores the mechanisms that help to explain this rarity, including unique SKM architecture and function, which prohibits the development of new cancer as well as negates potential metastasis to SKM. SKM also presents a unique immune environment that may magnify the anti-tumorigenic effect. Moreover, the SKM microenvironment manifests characteristics such as decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels that may interfere with tumor development. SKM also secretes anti-tumorigenic myokines and other molecules. Collectively, these mechanisms help account for the rarity of SKM cancer.

The choroid plexus (CP) is an understudied tissue in the central nervous system (CNS), primarily implicated in cerebrospinal fluid (CSF) production. Additionally, CP produces numerous neurotrophic factors (NTF), which circulate to different regions of the brain. Regulation of NTF in the CP during natural aging has yet to be discovered. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and water channel protein Aquaporin (AQP1).

We used male and female mice for our study. We analyzed neurotrophic factor gene expression patterns using quantitative and digital droplet PCR at three different time points: mature adult, middle-aged, and aged. Additionally, we used immunohistochemical analysis (IHC) to evaluate in vivo protein expression. We further investigated the cellular phenotype of these NTFS, TJP and water channel proteins in the mouse CP by co-labeling them with the classical vascular marker, Isolectin B4, and epithelial cell marker, plectin.

Aging significantly altered the NTF's gene expression in the CP Brain-derived neurotrophic factor (BDNF), Midkine, VGF, Insulin-like growth factor (IGF1), IGF2, klotho, Erythropoietin, and its receptor were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression is unchanged in the aged CP while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJP's JAM, CLAUDIN1, CLAUDIN2, and CLAUDIN5 were reduced in aged mice.

Our study highlights transcriptional level changes in the CP during aging. The age-related transcriptional changes exhibit similarities as well as gene-specific differences in the CP of males and females. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-β/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and tumour immune response, and are essential components in tumour progression and metastasis. As such, they have become a target for cancer therapy research. In this review, we discussed the current state of knowledge on the involvement of PPARs in cancer, including their role in tumourigenesis, the impact of PPARs in tumour microenvironment and the potential of using PPARs combinational therapy to treat cancer by targeting essential signal pathways, or as adjuvants to boost the effects of current chemo and immunotherapies. Our review highlights the complexity of PPARs in cancer and the need for a better understanding of the mechanism in order to design effective cancer therapies.

Lung cancer is responsible for the highest number of cancer-related deaths, with non-small cell lung cancer (NSCLC) being the most prevalent subtype. A critical aspect of managing lung cancer is reducing morbidity and mortality rates among NSCLC patients. Identifying high-risk factors for lung cancer and facilitating early diagnosis are invaluable in achieving this objective. Recent research has highlighted the association between insulin resistance and the development of NSCLC, further emphasizing its significance in the context of lung cancer. It has been discovered that improving insulin resistance can potentially inhibit the progression of lung cancer. Consequently, this paper aims to delve into the occurrence of insulin resistance, the mechanisms underlying its involvement in lung cancer development, as well as its potential value in predicting, assessing, and treating lung cancer.

One of the general characteristics of cancer cells is the abnormal increase of O-GlcNAcylation. Recent studies have shown that it affects the basic functions of proteins and regulates multiple phenotypes of cancer cells through key signals and metabolic pathways. O-GlcNAcylation is a covalent linkage between the β-D-N-acetylglucosamine (GlcNAc) sugar and target protein. It interacts with many other types of post-translational modifications and works together in the whole process of cancer development. For example, it regulates cell activities such as cell signal transduction, transcription, cell division, metabolism and cytoskeleton regulation. In this review, we summarized the general concept of O-GlcNAcylation and its related role in the ten major tumor phenotypes.

Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines.

The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal.

This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8+ and TCD8+CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors.

The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients.

PHF5A is a member of the zinc-finger proteins. To advance knowledge on their role in carcinogenesis, data from experimental studies, animal models and clinical studies in different tumorigenesis have been reviewed. Furthermore, PHF5A as an oncogenic function, is frequently high expressed in tumor cells and a potential prognostic marker for different cancers. PHF5A is implicated in the regulation of cancer cell proliferation, invasion, migration and metastasis. Knockdown of PHF5A prevented the invasion and metastasis of tumor cells. Here, the role of PHF5A in different cancers and their possible mechanism in relation to recent literature is reviewed and discussed. There is an open promising perspective to their therapeutic management for different cancer types.

Green tea, a popular and healthy nonalcoholic drink consumed globally, is abundant in natural polyphenols. One of these polyphenols is epigallocatechin-3-gallate (EGCG), which offers a range of health benefits, such as metabolic regulation, antioxidant properties, anti-inflammatory effects, and potential anticancer properties. Clinical research has shown that EGCG can inhibit cancers in the male and female reproductive systems, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Further research on cervical cancer has revealed the crucial role of epigenetic mechanisms in the initiation and progression of this type of cancer. These include changes to the DNA, histones, and non-coding RNAs, such as microRNAs. These changes are reversible and can occur even before genetic mutations, making them a potential target for intervention therapies. One promising approach to cancer prevention and treatment is the use of specific agents (known as epi-drugs) that target the cancer epigenome or epigenetic dysregulation. Phytochemicals, a group of diverse molecules, have shown potential in modulating cancer processes through their interaction with the epigenetic machinery. Among these, green tea and its main polyphenol EGCG have been extensively studied. This review highlights the therapeutic effects of EGCG and its nanoformulations on cervical cancer. It also discusses the epigenetic events involved in cervical cancer, such as DNA methylation and microRNA dysregulation, which may be affected by EGCG.

The proportion of patients diagnosed with cancer has been shown to rise with the increasing aging global population. Advanced age is a major risk factor for morbidity and mortality in older adults. As individuals experience varying health statuses, particularly with age, it poses a challenge for medical professionals in the cancer field to obtain standardized treatment outcomes. Hence, relying solely on chronological age and disease-related parameters is inadequate for clinical decision-making for elderly patients. With functional, multimorbidity-related, and psychosocial changes that occur with aging, oncologic diseases may develop and be treated differently from younger patients, leading to unique challenges in treatment efficacy and tolerance. To overcome this challenge, personalized therapy using biomarkers has emerged as a promising solution. Various categories of biomarkers, including inflammatory, hematological, metabolic, endocrine, and DNA modification-related indicators, may display features related to both cancer and aging, aiding in the development of innovative therapeutic approaches for patients with cancer in old age. Furthermore, physical functional measurements as non-molecular phenotypic biomarkers are being investigated for their potential complementary role in structured multidomain strategies to combat age-related diseases such as cancer. This review provides insight into the current developments, recent discoveries, and significant challenges in cancer and aging biomarkers, with a specific focus on their application in advanced age.

Regeneration is a homeostatic process that involves the restoration of cells and body parts. Most of the molecular mechanisms and signalling pathways involved in wound healing, such as proliferation, have also been associated with cancer cell growth, suggesting that cancer is an over/unhealed wound. In this study, we examined differentially expressed genes in spinal cord samples from regenerative organisms (axolotl and zebrafish) and nonregenerative organisms (mouse and rat) compared to intact control spinal cord samples using publicly available transcriptomics data and bioinformatics analyses. Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. The predicted target genes of the repositioned compounds were mainly enriched with the greatest number of genes in cancer pathways. The molecular docking results on the binding affinity between the repositioned compounds and their target genes are also reported. The repositioned 3 small compounds showed anticancer effect both in 2D and 3D cell cultures using the prostate cancer cell line as a model. We propose cucurbitacin I, BMS-754807, and PHA-793887 as potential anticancer drug candidates. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.

Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.

Analyzing gene expression profiles (GEP) through artificial intelligence provides meaningful insight into cancer disease. This study introduces DeepSHAP Autoencoder Filter for Genes Selection (DSAF-GS), a novel deep learning and explainable artificial intelligence-based approach for feature selection in genomics-scale data. DSAF-GS exploits the autoencoder's reconstruction capabilities without changing the original feature space, enhancing the interpretation of the results. Explainable artificial intelligence is then used to select the informative genes for chronic lymphocytic leukemia prognosis of 217 cases from a GEP database comprising roughly 20,000 genes. The model for prognosis prediction achieved an accuracy of 86.4%, a sensitivity of 85.0%, and a specificity of 87.5%. According to the proposed approach, predictions were strongly influenced by CEACAM19 and PIGP, moderately influenced by MKL1 and GNE, and poorly influenced by other genes. The 10 most influential genes were selected for further analysis. Among them, FADD, FIBP, FIBP, GNE, IGF1R, MKL1, PIGP, and SLC39A6 were identified in the Reactome pathway database as involved in signal transduction, transcription, protein metabolism, immune system, cell cycle, and apoptosis. Moreover, according to the network model of the 3D protein-protein interaction (PPI) explored using the NetworkAnalyst tool, FADD, FIBP, IGF1R, QTRT1, GNE, SLC39A6, and MKL1 appear coupled into a complex network. Finally, all 10 selected genes showed a predictive power on time to first treatment (TTFT) in univariate analyses on a basic prognostic model including IGHV mutational status, del(11q) and del(17p), NOTCH1 mutations, β2-microglobulin, Rai stage, and B-lymphocytosis known to predict TTFT in CLL. However, only IGF1R [hazard ratio (HR) 1.41, 95% CI 1.08-1.84, P=0.013), COL28A1 (HR 0.32, 95% CI 0.10-0.97, P=0.045), and QTRT1 (HR 7.73, 95% CI 2.48-24.04, P<0.001) genes were significantly associated with TTFT in multivariable analyses when combined with the prognostic factors of the basic model, ultimately increasing the Harrell's c-index and the explained variation to 78.6% (versus 76.5% of the basic prognostic model) and 52.6% (versus 42.2% of the basic prognostic model), respectively. Also, the goodness of model fit was enhanced (χ2 = 20.1, P=0.002), indicating its improved performance above the basic prognostic model. In conclusion, DSAF-GS identified a group of significant genes for CLL prognosis, suggesting future directions for bio-molecular research.

It is estimated that 25% of the world's population has non-alcoholic fatty liver disease. This disease can advance to a more severe form, non-alcoholic steatohepatitis (NASH), a disease with a greater probability of progression to cirrhosis and hepatocellular carcinoma (HCC). NASH could be characterized as a necro-inflammatory complication of chronic hepatic steatosis. The combination of factors that lead to NASH and its progression to HCC in the setting of inflammation is not clearly understood. The portal vein is the main route of communication between the intestine and the liver. This allows the transfer of products derived from the intestine to the liver and the hepatic response pathway of bile and antibody secretion to the intestine. The intestinal microbiota performs a fundamental role in the regulation of immune function, but it can undergo changes that alter its functionality. These changes can also contribute to cancer by disrupting the immune system and causing chronic inflammation and immune dysfunction, both of which are implicated in cancer development. In this article, we address the link between inflammation, microbiota and HCC. We also review the different in vitro models, as well as recent clinical trials addressing liver cancer and microbiota.

The development of new antitumor drugs depends mainly upon targeting tumor cells precisely. Trophoblast surface antigen 2 (Trop-2) is a type I transmembrane glycoprotein involved in Ca2+ signaling in tumor cells. It is highly expressed in various tumor tissues than in normal tissues and represents a novel and promising molecular target for caner targeted therapy. Up to now, the mechanisms and functions associated with Trop-2 have been extensively studied in a variety of solid tumors. According to these findings, Trop-2 plays an important role in cell proliferation, apoptosis, cell adhesion, epithelial-mesenchymal transition, as well as tumorigenesis and tumor progression. In addition, Trop-2 related drugs are also being developed widely. There are a number of Trop-2 related ADC drugs that have demonstrated potent antitumor activity and are currently been studied, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-Dxd). In this study, we reviewed the progress of Trop-2 research in solid tumors. We also sorted out the composition and rationale of Trop-2 related drugs and summarized the related clinical trials. Finally, we discussed the current status of Trop-2 research and expanded our perspectives on its future research directions. Importantly, we found that Trop-2 targeted ADCs have great potential for combination with other antitumor therapies. Trop-2 targeted ADCs can reprogramme tumor microenvironment through multiple signaling pathways, ultimately activating antitumor immunity.

Pulmonary emphysema is a destructive inflammatory disease primarily caused by cigarette smoking (CS). Recovery from CS-induced injury requires proper stem cell (SC) activities with a tightly controlled balance of proliferation and differentiation. Here we show that acute alveolar injury induced by two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (N/B), increased IGF2 expression in alveolar type 2 (AT2) cells to promote their SC function and facilitate alveolar regeneration. Autocrine IGF2 signaling upregulated Wnt genes, particularly Wnt3, to stimulate AT2 proliferation and alveolar barrier regeneration after N/B-induced acute injury. In contrast, repetitive N/B exposure provoked sustained IGF2-Wnt signaling through DNMT3A-mediated epigenetic control of IGF2 expression, causing a proliferation/differentiation imbalance in AT2s and development of emphysema and cancer. Hypermethylation of the IGF2 promoter and overexpression of DNMT3A, IGF2, and the Wnt target gene AXIN2 were seen in the lungs of patients with CS-associated emphysema and cancer. Pharmacologic or genetic approaches targeting IGF2-Wnt signaling or DNMT prevented the development of N/B-induced pulmonary diseases. These findings support dual roles of AT2 cells, which can either stimulate alveolar repair or promote emphysema and cancer depending on IGF2 expression levels.

IGF2-Wnt signaling plays a key role in AT2-mediated alveolar repair after cigarette smoking-induced injury but also drives pathogenesis of pulmonary emphysema and cancer when hyperactivated.

The results regarding the association between insulin-like growth factor binding protein 1 (IGFBP1) expression and cancer risk were controversial. We performed a meta-analysis to provide novel evidence on relationship between IGFBP1 expression and cancer risk.

PubMed, Embase, Cochrane library and Web of science were searched for relevant cohort and case-control studies exploring the relationship between IGFBP1 expression and cancer risk. Odds ratios (ORs) were pooled in this meta-analysis using random model. Subgroup analyses were performed based on ethnicity, tumor types, publication year, study type, Newcastle-Ottawa Scale (NOS) score and sex.

A total of 27 studies including 16 cohort and 11 case-control studies were identified by literature search. No significant association was found between IGFBP1 expression and risk of various cancers [0.90, 95% confidence interval (CI): 0.79, 1.03]. The overall results showed that the pooled ORs were 0.71 (95% CI: 0.57, 0.88] for prostate cancer risk and 0.66 (95%CI: 0.44, 0.99) for colorectal cancer (CRC) risk. However, there is no significant association between IGFBP1 expression and risk for ovarian cancer (1.70, 95%CI: 0.41, 6.99), breast cancer (1.02, 95%CI: 0.85, 1.23), endometrial cancer (1.19, 95%CI: 0.64, 2.21), colorectal adenoma (0.93; 95%CI: 0.81, 1.07), lung cancer (0.81, 95%CI: 0.39, 1.68) or multiple myeloma (1.20, 95%CI: 0.98, 1.47).

In this study, compared with individuals at low IGFBP1 expression adjusted for age, smoking status, alcohol intake and so on, risk of the prostate cancer and CRC were decreased among individuals of high IGFBP1 expression. There needs further study to confirm this issue.

The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers.

While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies.