Tumor Angiogenesis Factor Research Articles

Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment.

Emerging evidence suggests that nerves within the tumor microenvironment play a crucial role in regulating angiogenesis. Neurotransmitters and neuropeptides released by nerves can interact with nearby blood vessels and tumor cells, influencing their behavior and modulating the angiogenic response. Moreover, nerve-derived signals may activate signaling pathways that enhance the production of pro-angiogenic factors within the tumor microenvironment, further supporting blood vessel growth around tumors. The intricate network of communication between neural constituents and the vascular system accentuates the potential of therapeutically targeting neural-mediated pathways as an innovative strategy to modulate tumor angiogenesis and, consequently, neoplastic proliferation. Hereby, we review studies that evaluate the precise molecular interplay and the potential clinical ramifications of manipulating neural elements for the purpose of anti-angiogenic therapeutics within the scope of cancer treatment.

Roles of endothelial cell specific molecule‑1 in tumor angiogenesis (Review).

Angiogenesis plays a crucial role in tumor growth and metastasis, and is heavily influenced by the tumor microenvironment (TME). Endothelial cell dysfunction is a key factor in tumor angiogenesis and is characterized by the aberrant expression of pro-angiogenic factors. Endothelial cell specific molecule-1 (ESM1), also known as endocan, is a marker of endothelial cell dysfunction. Although ESM1 is primarily expressed in normal endothelial cells, dysregulated ESM1 expression has been observed in human tumors and animal tumor models, and implicated in tumor growth, metastasis and angiogenesis. The precise role of ESM1 in tumor angiogenesis and its potential regulatory mechanisms are not yet conclusively defined. However, the aim of the present review was to explore the involvement of ESM1 in the process of tumor angiogenesis in the TME and the characteristics of neovascularization. In addition, the present review discusses the interaction between ESM1 and angiogenic factors, as well as the mechanisms through which ESM1 contributes to tumor angiogenesis. Furthermore, the reciprocal regulation between ESM1 and the TME is explored. Finally, the potential of targeting ESM1 as a therapeutic strategy for tumor angiogenesis is presented.

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells in tumor tissues.

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed in vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells in vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents and the optimal dosage and administration schedule of antineoplastic agents need to be determined through further research.

U-Net based vessel segmentation for murine brains with small micro-magnetic resonance imaging reference datasets.

Identification and quantitative segmentation of individual blood vessels in mice visualized with preclinical imaging techniques is a tedious, manual or semiautomated task that can require weeks of reviewing hundreds of levels of individual data sets. Preclinical imaging, such as micro-magnetic resonance imaging (μMRI) can produce tomographic datasets of murine vasculature across length scales and organs, which is of outmost importance to study tumor progression, angiogenesis, or vascular risk factors for diseases such as Alzheimer's. Training a neural network capable of accurate segmentation results requires a sufficiently large amount of labelled data, which takes a long time to compile. Recently, several reasonably automated approaches have emerged in the preclinical context but still require significant manual input and are less accurate than the deep learning approach presented in this paper-quantified by the Dice score. In this work, the implementation of a shallow, three-dimensional U-Net architecture for the segmentation of vessels in murine brains is presented, which is (1) open-source, (2) can be achieved with a small dataset (in this work only 8 μMRI imaging stacks of mouse brains were available), and (3) requires only a small subset of labelled training data. The presented model is evaluated together with two post-processing methodologies using a cross-validation, which results in an average Dice score of 61.34% in its best setup. The results show, that the methodology is able to detect blood vessels faster and more reliably compared to state-of-the-art vesselness filters with an average Dice score of 43.88% for the used dataset.

M2 macrophage inhibits the antitumor effects of Lenvatinib on intrahepatic cholangiocarcinoma.

The relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors. Tumor-associated macrophages (TAMs) are important inflammatory cells in the tumor microenvironment and play an important role in tumorigenesis and progression. Macrophages in malignant tumors, mainly the M2 subtype, promote tumor progression by producing cytokines and down-regulating anti-inflammatory immune responses. Several articles have investigated the effect of macrophages on the sensitivity of cancer chemotherapeutic agents, but few such articles have been reported in cholangiocarcinoma, so we investigated the effect of M2 macrophage on the sensitivity of cholangiocarcinoma cells to Lenvatinib compared to M1. THP-1 monocytes were polarized to M0 macrophage by phorbol 12-myristate 13-acetate (PMA) and then induced to differentiate into M1 and M2 macrophages by LPS, IFN-γ and IL-4 and IL-13, respectively. Macrophages and cholangiocarcinoma cells were co-cultured prior to 24 hours of Lenvatinib administration, cancer cell apoptosis was detected by western-blot, FACS analysis of Annexin V and PI staining. Furthermore, we use xCELLigence RTCA SP Instrument (ACEA Bio-sciences) to monitor cell viability of Lenvatinib administration in co-culture of cholangiocarcinoma cells and macrophages. After tumorigenesis in immunodeficient mice, Lenvatinib was administered, and the effects of M2 on biological characteristics of cholangiocarcinoma cells were investigated by immuno-histochemistry. mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1 derived macrophages, which provided a successful and efficient model of monocyte polarization to TAMs. Lenvatinib-induced apoptosis of cholangiocarcinoma cells was significantly reduced when co-cultured with M2 macrophage, whereas apoptosis of cholangiocarcinoma cells co-cultured with M1 macrophage was increased. In the CDX model, Lenvatinib-induced cancer cell apoptosis was markedly reduced, and proliferative cells increased in the presence of M2 macrophages. Angiogenesis related factors was significantly increased in cholangiocarcinoma cells co-cultured with M2. Compared with M1, M2 macrophages can inhibit the anti-tumor effect of Lenvatinib on cholangiocarcinoma through immune regulation, which may be related to the tumor angiogenesis factor effect of M2 macrophage.

AATF inhibition exerts antiangiogenic effects against human hepatocellular carcinoma.

Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC. HCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques. We identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF KD cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD. Our study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.

RNAi gene therapy in Cancer treatment

Cancer is caused by failures in the genetic control of cell division processes, which alter the function of proto-oncogenes and tumor suppressor genes. Cancer causes and treatments have been studied for years, but the development of effective therapies has its limitations, and conventional therapies frequently have significant side effects. In the search for efficient therapeutic alternatives against cancer cells, the use of non-coding RNA (ncRNA), particularly RNA interference (RNAi), has shown promise. Therefore, the current study aimed to characterize RNAi and their applications in gene therapy against cancer through a descriptive bibliographical review. RNAi consists of a gene silencing mechanism that generally occurs through two pathways: the production of microRNAs (miRNA) and small interfering RNAs (siRNA). Several satisfactory and promising studies have been developed with the use of RNAi in cancer diagnosis and therapy. In general, the strategies investigated in these studies focus on the silencing of genes related to the inhibition of tumor apoptosis, oncogene silencing, inhibition of tumor angiogenesis factors, and chemoresistance reduction. Although the success of using RNAi in the fight against cancer is dependent on the efficiency with which these molecules are delivered to the target tissue, research in this area has been advancing, bringing the possibility of more efficient therapies with fewer side effects increasingly closer.

Rice field snail shell anticancer properties: An exploration opinion.

Calcium carbonate is also the primary material used to synthesize hydroxyapatite, a biocompatible material with high binding activity to proteins and genetic materials. Nanoparticle hydroxyapatite showed in vitro and in vivo anti-proliferative potential against cancer cells (Kargozar, S. et al., 2020; Zhao, H. et al., 2018). Various studies have shown that snail shells also contain bioactive compounds like chitin – the primary material of chitosan – that offers antipathogenic, antioxidant properties, as well as pharmaceutical additive potential (Jatto, O.E. et al., 2010; Abd El-Hack. M.E. et al., 2020). Furthermore, chitin and its derivatives were found to have a significant immunomodulating response against cancer and antitumor activity through the downregulation of tumor angiogenesis factors, apoptotic effects stimulation, and decreased cell adhesion (Satitsri, S. and Muanprasat, C., 2020). However, the bioactive component's profile of snail shells is partially influenced by their habitat, surrounding environment, mineral content, and microorganisms (Sundalian, M. et al., 2021). Therefore, this article specifically aims to summarize the recent findings on potential anticancer properties in molecular and cellular oncology mechanisms of rice field snail shells.

Mathematical analysis to the variation of tumor cells density according to recovery of five organs: Kidney, liver, heart, spleen, and lung

Background and objectiveHarmonious interactions of five representative organs: kidney, liver, heart, spleen, and lung, improve metastasis and cell divisions, and abnormal cell division causes cancer cell development. The research is processed through a mathematical approach based on win-win principle of five organs to generate medicine in blood vessel. The variations of solute medicine amount in blood vessel with respect to the flow rates of injected drugs are interpreted. The alterations of tumor cells density and tumor angiogenesis factor concentration are described according to the recovery of five organs’ functions. MethodsA compartmental analysis is applied to obtain medicine concentration in blood vessel by the functional recovery of five organs considering time level ti, the reaction rate coefficient Rj, and the medicine flow rate α. Random motility and chemotaxis in response to tumor angiogenesis factor gradients are comprised to derive mathematical governing equations for tumor cells motion and a finite volume method with time-changing is adopted to obtain numerical solutions due to the complexity of the governing equations. ResultsDrug concentration in blood vessel grows as heart reaction rate increases, and the medicine made through the functional enhancements of five representative organs is highly influential to restrain the activity of tumor angiogenesis factor. With the growth of medicine concentration in blood vessel according to the decline of reaction rate and medicine flow rate, tumor cells reacts hypersensitively at the moment of medicines injection and the density of tumor cells approached to zero. ConclusionsConsequently, reaction rate, time level, and medicine flow rate are crucial factors in the determination of medicine amount in blood vessel and to control tumor angiogenesis factor concentration, and harmonious balanced functions among five organs based on win-win principle contribute to control the activity of tumor cells.

A two-dimensional mathematical model of tumor angiogenesis with CD147.

Tumor angiogenesis is the tumor's inherent blood supply system which is crucial for the growth of tumor. Extracellular Matrix Metallo Proteinases Inducer (EMMPRIN)/Cluster of Differentiation 147 (CD147) is found in high levels on tumor surfaces. This study focuses on these elevated levels of CD147 and the effect it has on tumor angiogenesis. The present article develops a Two-Dimensional Mathematical Model of Tumor Angiogenesis taking into account the CD147 molecule. The effects of CD147 on Tumor Angiogenesis Factors (TAFs), fibronectin and Matrix Metallo Proteinases (MMPs) are also incorporated. The results have been obtained through COMSOL Multiphysics 5.4 software. The results show that CD147 is responsible for swifter angiogenesis, calling for targeting this molecule in anti-angiogenic strategies. The present model is validated with the existing theoretical and experimental results.

Construction and validation of a prognostic risk model of angiogenesis factors in skin cutaneous melanoma.

Melanoma can secrete tumor angiogenesis factors, which is the essential factor for tumor growth and metastasis. However, there are few reports on the relationship between angiogenesis factors and prognosis risk in melanoma. This study aimed to develop a prognostic risk model of angiogenesis for melanoma. Forty-nine differentially expressed angiogenesis were identified from the TCGA database, which were mainly involved in PI3K/Akt pathway, focal adhesion, and MAPK signaling pathway. We then establish an eleven-gene signature. The model indicated a strong prognostic capability in both the discovery cohort and the validation cohort. Patients of smaller height (<170 cm) and lower weight (<80 kg) and those with advanced-stage and ulcerated melanoma had higher risk scores. The risk score was positively correlated with mutation load, homologous recombination defect, neoantigen load and chromosome instability. In addition, the high-risk group had a higher degree of immune cell infiltration, better response to immunotherapy and lower immune score. Therefore, these results indicate that the risk model is an effective method to predict the prognosis of melanoma.

Pulmonary lesions: correlative study of dynamic triple-phase enhanced CT perfusion imaging with tumor angiogenesis and vascular endothelial growth factor expression

BackgroundTo investigate value of the quantitative perfusion parameters of dynamic triple-phase enhanced CT in differential diagnosis of pulmonary lesions, and explore the correlation between perfusion parameters of lung cancer with microvessel density (MVD) and vascular endothelial growth factor (VEGF).Methods73 consecutive patients with lung lesions who successfully underwent pre-operative CT perfusion examination with dynamic triple-phase enhanced CT and received a final diagnosis by postoperative pathology or a clinical follow-up. The cases were divided into malignant and benign groups according to the pathological results. CT perfusion parameters, such as Median, Mean, Standard deviation (Std), Q10, Q25, Q50, Q75, Q90 of pulmonary artery perfusion (PAP), bronchial artery perfusion (BAP), perfusion index (PI) and arterial enhancement fraction (AEF) were obtained by performing computed tomography perfusion imaging (CTPI). Computed tomography perfusion (CTP) parameters were compared between malignant and benign lesions. The receiver operating characteristic (ROC) curve was used to assess the diagnostic efficiency of CTP parameters in diagnosing malignant lesions. The correlations between CTP parameters with MVD and VEGF were analysed in 36 lung cancer patients who had extra sections be used for immunohistochemistry staining of CD34 and VEGF.ResultsBAP (Mean, Std, Q90) and PI Std of benign lesions were higher than malignant lesions (p < 0.05), and PAP (Q10, Q25), PI (Median, Mean, Q10, Q25, Q50) of malignant lesions were higher than the benign (p < 0.05). The area under the ROC curve of PI Mean, PI Q10 and PI Std was 0.722 (95% CI = [0.595–0.845]), 0.728 (95% CI = [0.612–0.844]) and 0.717 (95% CI = [0.598–0.835]) respectively. Partial perfusion parameters of BAP and AEF Q10 were positively correlated with MVD (p value range is < 0.001–0.037, ρ value range is 0.483–0.683), and partial perfusion parameters of PI were negatively correlated with MVD (p value range is 0.001–0.041,ρvalue range is − 0.523–− 0.343). Partial perfusion parameters of BAP and AEF Q10 were positively correlated with VEGF (p value range is 0.001–0.016, ρvalue range is 0.398–0.570), meanwhile some perfusion parameters of PAP and PI were negatively correlated with VEGF (p value range is 0.001–0.040, ρ value range is − 0.657–0.343).ConclusionsQuantitative parameters of dynamic triple-phase enhanced CT can provide diagnostic basis for the differentiation of lung lesions, and there were connection with tumor angiogenesis and vascular endothelial growth factor expression.

AVB-500, a selective inhibitor of GAS6-AXL, shows improved therapeutic efficacy in combination with paclitaxel in uterine serous carcinoma

<h3>Objectives:</h3> The receptor tyrosine kinase AXL is highly expressed in uterine serous cancer (USC) and has been found to mediate chemoresistance. Recently, in a Phase I clinical trial in ovarian cancer, AVB-500 has been shown in combination with paclitaxel to be safe and tolerable. The objectives of this study were to determine if AVB-500 improves response to paclitaxel in USC in preclinical studies and to explore how GAS6/AXL expression modulates the immune environment via changes in cytokine secretion profiling. <h3>Methods:</h3> AVB-500 (AVB) was supplied by Aravive Biologics. XTT cell viability was performed with two USC tumor cells - ARK1 and primary cells derived from ascites of a patient with platinum refractory USC (PUC1). Cells were treated with paclitaxel (P) alone and with a combination of AVB-500 and paclitaxel (AVB+P). Western blot analysis for apoptosis marker, cleaved PARP (c-PARP) was completed with ARK1 cells treated with AVB, P, and AVB+P. <i>in vivo</i> studies were performed using NOD-SCID mice injected with 1 x 107 ARK1 cells intraperionteally (IP). Treatment groups included vehicle, AVB, P, and AVB+P. Tumor nodule number, volume, and weight were assessed for each treatment group. Profiling of 80 inflammatory cytokines was performed with conditioned media (CM) collected from ARK1 control and AXL knockdown (KD) cells using Human Cytokine Array C5 (RayBiotech). Per manufacturer's criteria, proteins were significantly upregulated if the signal intensity ≥1.50 fold, and significantly downregulated if the signal intensity ≤0.65 fold. <h3>Results:</h3> We found that the USC cell line ARK1 had decreased viability when treated with A+P than when treated with P alone (IC50 11.5nM vs 39.2nM). In addition, the relative percent viability was lower in the AVB+P treated cells for every concentration of P (0.156 nM to 320 nM, p<0.05). Similarly, PUC1 had decreased viability when treated with AVB+P than with P alone (IC50 20.9nM vs 43.3nM). Western blot revealed greater apoptosis in the AVP+P treated cells as seen by c-PARP expression when compared to P alone. An <i>in vivo</i> metastatic IP model had significantly fewer tumors when treated with AVB+P compared to P alone with number of tumor nodules ≤1mm (2.750 vs 7.889, p=0.028) as well as decreased tumor weight (0.025 g vs 0.079 g, p<0.001) and smaller tumor volume (16.75 mm3 vs 72.33 mm3, p=0.002). Mouse weights were similar between treatment groups, indicating a favorable safety profile of the AVB+P combination. Furthermore, the CM from ARK1 cells with and without AXL expression were compared and the following significant changes were identified in the AXL non-expressing CM: decrease in cytokines involved in tumor cell proliferation and survival (TNF<b>-</b>α TNF-β<b>,</b> IGF, HGF, and TGF<b>-</b>β3), decrease in pro-tumor cytokines (IL-10, IL-13, and IL-16), and a decrease in angiogenesis factors (angiogenin, PDGF, FGF-6, and FGF-7). <h3>Conclusions:</h3> The combination of AVB-500 and paclitaxel has demonstrates a superior therapeutic efficacy compared to paclitaxel alone in USC pre-clinical models. In addition, cytokine expression profiles for tumor cell proliferation, pro-tumor cytokines, and angiogenesis factors suggest a mechanism by which GAS6/AXL signaling leads to immune suppression and evasion. Experiments in additional USC cell lines and patient-derived xenograft models are ongoing.

Abstract 5: Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors

Abstract Tumor angiogenesis is regulated by multiple pro- and anti-angiogenic factors. Anti-angiogenic drugs target the interconnected network of these angiogenic factors to inhibit neovascularization and tumor growth. However, current anti-angiogenic therapeutics targeting a single angiogenic factor show limited clinical success, prompting the development of combination anti-angiogenic therapy targeting multiple angiogenic factors simultaneously. In cases where anti-angiogenic therapy may be effective, tumors display a wide range of responses, which is not fully understood. In this work, we use an integrative in vitro imaging and mathematical modeling approach to investigate how tumor angiogenesis is systematically regulated by multiple angiogenic factors and to study the effects of anti-angiogenic therapy. We particularly focus on two pro-angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors, thrombospondin-1 (TSP1) and platelet factor 4 (PF4). In our in vitro experimental setting human endothelial cells are cultured in a microfluidic organ-on-chip chip platform exposed to angiogenic factors or in the presence of cancer cells to mimic the tumor microenvironment. The cellular responses induced by various concentrations of angiogenic factors are measured through a high content screening (HCS) confocal imaging system to quantify the cell counts, morphological features and vessel characteristics. These data are used to construct a novel mathematical model to capture how the angiogenic factors mediate cross-talk between tumor cells and endothelial cells. By fitting the model to the experimental measurements, we are able to predict the temporal dynamics of cell numbers and concentrations of the angiogenic factors. Using the model, we generate insights into the effects of angiogenic factors and various anti-angiogenic treatments on tumor cells and endothelial cells. Excitingly, the model can also be applied to investigate how the effect of anti-angiogenic therapy is influenced by inter-tumor heterogeneity. For example, we identified that tumors with lower tumor cell growth rate and higher carrying capacity have a stronger response to anti-VEGF treatment, which indicates that variation in tumor cell growth rates can be a main reason for the observed heterogenous response to anti-VEGF therapy. In addition, we investigate a novel hypothesis regarding synergy between anti-angiogenic and chemotherapeutic agents with the model. Our simulated results suggest a new mechanism in which the chemotherapeutic agent enhances anti-angiogenic therapy simply through reducing the tumor cell growth rate. Overall, this work generates novel insights into the function of multiple angiogenic factors in tumor angiogenesis, providing a tool that can be further used to test and optimize anticancer therapy. Citation Format: Ding Li, Danielle D. Hixon, Shannon M. Mumenthaler, Stacey D. Finley. Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 5.

Modeling and simulation of vascular tumors embedded in evolving capillary networks

In this work, we present a coupled 3D–1D model of solid tumor growth within a dynamically changing vascular network to facilitate realistic simulations of angiogenesis. Additionally, the model includes erosion of the extracellular matrix, interstitial flow, and coupled flow in blood vessels and tissue. We employ continuum mixture theory with stochastic Cahn–Hilliard type phase-field models of tumor growth. The interstitial flow is governed by a mesoscale version of Darcy’s law. The flow in the blood vessels is controlled by Poiseuille flow, and Starling’s law is applied to model the mass transfer in and out of blood vessels. The evolution of the network of blood vessels is orchestrated by the concentration of the tumor angiogenesis factors (TAFs); blood vessels grow towards the increasing TAFs concentrations. This process is not deterministic, allowing random growth of blood vessels and, therefore, due to the coupling of nutrients in tissue and vessels, makes the growth of tumors stochastic. We demonstrate the performance of the model by applying it to a variety of scenarios. Numerical experiments illustrate the flexibility of the model and its ability to generate satellite tumors. Simulations of the effects of angiogenesis on tumor growth are presented as well as sample-independent features of cancer.

Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.

Modern perspectives in sequential therapy for metastatic colorectal cancer with reference to the use of regorafenib

Over the past two decades, many new variants of targeted therapy for metastatic colorectal cancer (mCRC) had appeared, and significantly increased patient survival. However, there were questions relating to the definition of the optimal sequence and the combination of different drugs. Cytotoxic agents, including irinotecan, oxaliplatin, 5-fluorouracil and capecitabine, are the basis of the treatment of mCRC. In addition, the arsenal of modern oncologist includes the group of drugs inhibiting the epidermal growth factors (for example, cetuximab and panitumumab) and inhibiting tumor angiogenesis factors (for example, bevacizumab and aflibercept). Moreover, the use of immuno-oncology drugs, trastuzumab or encorafenib is possible in case of knowing tumor-specific molecular signature. Unfortunately, these new indications can be used only in small proportion of patients. The multikinase inhibitor regorafenib takes a special place, it can be used in patients in spite of RAS mutation status. The increasing attention has been paid to the selection of the drugs for sequential therapy of mCRC, recently. This review discusses important clinical data on the direct role of targeted drugs in the treatment of mCRC in different subgroups of patients.

Dysregulated PDGFR alpha\xa0expression and\xa0novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor\xa0size

BackgroundPlatelet derived growth factor receptor alpha (PDGFRα) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFRα protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction.MethodsOur study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFRα expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls.ResultsPDGFRα staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFRα overexpression. This overexpression was significantly associated with mutations in exon 18 (P = 0.024), RAS wild type status (P < 10–3), tumor diameter (P = 0.048), whereas there was no association with tumor side (P = 0.13) and other clinicopathological features.ConclusionOverexpression of PDGFRα in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFRα overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC.

Tryptase plays a role in solid tumor angiogenesis and cell proliferation

Tryptase, a serine protease released during mast cell degranulation has been associated with anaphylactic reactions and inflammations. In recent studies on solid tumor proliferation, it has been seen that tryptase has a role in tumor angiogenesis and tumor cell proliferation. This also makes tryptase a potential therapeutic target. Many anti-tryptase agents have shown to decrease tumor angiogenesis and proliferation. Authors have thus reviewed various articles which have done extensive studies on the role of tryptase as an important factor in tumor proliferation and angiogenesis.