Low-dose Cisplatin Induces Tumor Growth via Mobilization of Proangiogenic Bone Marrow-derived Cells in Mouse Models.

BACKGROUND/AIM: It is generally accepted that low-dose metronomic (LDM) chemotherapy mostly exerts its antitumor effects by inhibiting tumor angiogenesis. However, there is some evidence that LDM chemotherapy subsequently promotes tumor angiogenesis under certain regimens in animal models. The mechanisms responsible for these contradictory results are unclear. MATERIALS AND METHODS: Cisplatin (CDDP) was intraperitoneally administered to tumor-bearing mice at doses of 0.05-3 mg/kg every other day. The effects of LDM chemotherapy with CDDP on tumor growth and angiogenesis were observed. To determine the involved mechanisms, we analyzed the expression of vascular basement membrane proteins, transcription of angiogenesis-related genes in tumor tissues, and mobilization of proangiogenic bone marrow-derived cells (BMDCs) in circulating blood. RESULTS: The mean tumor weight with the 3 mg/kg q.o.d. regimen CDDP was significantly lower (by 57.3%) in the CDDP than in the control group. However, the tumor weight was 52.1% higher for the 0.19 mg/kg q.o.d. regimen in the CDDP group, which could be antagonized using 30 mg/kg all-trans retinoic acid. For the 0.19 mg/kg q.o.d., more tumor vascular structures were observed in the CDDP than in the control group (47.9±5.0 vs. 22.3±0.8, p<0.001). The mobilization of VEGFR2+ BMDCs and the mRNA expression of the proangiogenic genes MMP9, VEGFR1, VEGFR2 and VE-cadherin were increased in the 0.19 mg/kg regimen. CONCLUSION: These results indicate that metronomic CDDP promoted tumor angiogenesis and tumor growth via increased mobilization of proangiogenic BMDCs at certain low doses. This implies a potential therapeutic risk from an inappropriate LDM chemotherapy dosage and suggests that optimizing the LDM chemotherapy regimen is urgently needed.

Lipid Mediators Metabolic Chaos of Asthmatic Mice Reversed by Rosmarinic Acid.

BACKGROUND AND OBJECTIVE: Asthma is a common chronic inflammatory disease of the airways with no known cure. Lipid mediators (LMs) are a kind of inflammatory signaling molecules which are believed to be involved in the development of asthma. Hyssopus cuspidatus Boriss. is a traditional Uyghur medicine, which is widely used in the treatment of asthma and other respiratory diseases. Extraction of Hyssopus cuspidatus Boriss. was reported to neutralize asthma symptoms. The purpose of the study was to investigate both the anti-inflammatory and immunoregulation properties of the Hyssopus cuspidatus Boriss. extract (SXCF) and its main active constituent, rosmarinic acid (RosA), in vivo. The effect of RosA, a major constituent of SXCF, was evaluated on an asthmatic model, with both anti-inflammatory and immunoregulation properties. MATERIALS AND METHODS: Anti-inflammatory effect of SXCF and RosA was assessed using OVA-induced asthma model mice by UPLC-MS/MS method. RESULTS: Overall, RosA played a critical role in anti-asthma treatment. In total, 90% of LMs species that were significantly regulated by SXCF were covered. On the most important LMs associated with asthma, RosA equivalent induced similar effects as SXCF did. It is believed that some constituents in SXCF could neutralize RosA excessive impacts on LMs.

Biological Intelligence Inspired Trajectory Design for Energy Harvesting UAV Networks.

In this paper, the problem of trajectory design for energy harvesting unmanned aerial vehicles (UAVs) is studied. In the considered model, the UAV acts as a moving base station to serve the ground users, while collecting energy from the charging stations located at the center of a user group. For this purpose, the UAV must be examined and repaired regularly. In consequence, it is necessary to optimize the trajectory design of the UAV while jointly considering the maintenance costs, the reward of serving users, the energy management, and the user service time. To capture the relationship among these factors, we first model the completion of service and the harvested energy as the reward, and the energy consumption during the deployment as the cost. Then, the deployment profitability is defined as the ratio of the reward to the cost of the UAV trajectory. Based on this definition, the trajectory design problem is formulated as an optimization problem whose goal is to maximize the deployment profitability of the UAV. To solve this problem, a foraging-based algorithm is proposed to find the optimal trajectory so as to maximize the deployment profitability and minimize the average user service time. The proposed algorithm can find the optimal trajectory for the UAV with low time complexity at the level of polynomial. Fundamental analysis shows that the proposed algorithm achieves the maximal deployment profitability. Simulation results show that, compared to Q-learning algorithm, the proposed algorithm effectively reduces the operation time and the average user service time while achieving the maximal deployment profitability.

Antineoplastic agents in chemotherapy facilitating tumor growth and angiogenesis in the interval administrations.

AIMS: There is emerging evidence that antineoplastic agents and the cytotoxic effects on tumor tissues attenuate the benefits of chemotherapy due to tumor microenvironment changes. Nevertheless, the actual relationship between chemotherapy and recurrent tumors in which the genotypes differ from the original tumor after chemotherapy is unclear. MATERIALS AND METHODS: Bone marrow transplantation, flow cytometer, immune inhibition and immunofluorescence will be utilized to investigate the effect of antineoplastic agents on bone-marrow-derived cells (BMDCs) release and recruitment, and to explore the pathways and mechanisms of antineoplastic agents in promoting tumor growth. KEY FINDINGS: Tumor growth and angiogenesis were significantly enhanced in the mouse model after treatment with antineoplastic agents such as cyclophosphamide, 5-fluorouracil, or cisplatin, along with large increases in proangiogenic vascular endothelial growth factor receptor-2 (VEGFR2+), ß3+, CD11b+Gr-1+, and VEGFR2+ß3+ BMDCs in circulating blood. BMDC recruitment and VEGFR2 and ß3 mRNA transcription in tumor tissues were also enhanced by antineoplastic agents. Antineoplastic-agent-treated BMDCs markedly augmented tumor and endothelial cell proliferation, and ß3 mRNA transcription in endothelial cells (ECs). SIGNIFICANCE: The results suggested that antineoplastic-agent treatment augmented the tumor microenvironment by mobilizing proangiogenic BMDCs, enhancing BMDC recruitment and angiogenesis, and increasing BMDC-mediated tumor and EC functions. These results led to tumor growth and angiogenesis aggravation. It is paramount to elucidate the potential mechanism by which the cellular and molecular effects triggered by the antineoplastic agents attenuate the effects of cancer therapy, and thereafter to explore possible methods for improving tumor treatment efficacy.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women.

AIM: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs. METHOD: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature. RESULTS: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data. CONCLUSIONS: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women.

Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

Protective effect of polysaccharides of sea cucumber Acaudina leucoprocta on hydrogen peroxide-induced oxidative injury in RAW264.7 cells.

The aim of this experiment was to investigate the protective effects of polysaccharides of sea cucumber Acaudina leucoprocta (ALP) against hydrogen peroxide (H2O2) induced oxidative injury in RAW264.7 cells. Analysis of monosaccharide composition and structure of one fraction from ALP (ALPN) were analyzed by High Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectoscopy (FT-IR). The results showed that ALPN contain sulfate groups, which is sulfated polysaccharides. The results from MTT assay indicated that ALPN could markedly increase viability of cells compared with RAW264.7 cells exposed to H2O2. Moreover, ALPN significantly increased the levels of catalase (CAT), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD), decreased the production of malondialdehyde (MDA) and lactate dehydrogenase (LDH) in RAW264.7 cells. The data from RT-PCR showed that ALPN (300 µg/mL) could increase the gene expression levels of SOD1 and GPX1. ALPN could also observably increase the protein expression level of Nrf2 and decrease the protein expression level of Keap1 with western blot. Collectively, this study suggested that polysaccharides of sea cucumber Acaudina leucoprocta (ALP) could effectively protect RAW264.7 cells against H2O2-induced oxidative injury. This protection mechanism may be related to activation of the Nrf2/Keap1 signaling pathway.

Diffusion weighted cardiovascular magnetic resonance imaging for discriminating acute from non-acute deep venous Thrombus.

BACKGROUND: The importance of discriminating acute from non-acute thrombus is highlighted. The study aims to investigate the feasibility of readout-segmented diffusion weighted (DW) cardiovascular magnetic resonance (CMR) for discrimination of acute from non-acute deep venous thrombus (DVT). METHODS: For this prospective study from December 2015 to December 2017, 85 participants (mean age = 53 years, age range = 34~74) with DVT of lower extremities underwent readout-segmented DW CMR. DVT of ≤14 days were defined as acute (n = 55) and > 14 days as non-acute (n = 30). DVT visualization on b = 0, b = 800, and apparent diffusion coefficient (ADC) images were assessed using a 4-point scale (0~3, poor~excellent). DW CMR parameters were measured using region of interest (ROI). Relative signal intensity (rSI) and ADC were compared between acute and non-acute DVT using a Mann Whitney test. Sensitivity and specificity for ADC and rSI were calculated. RESULTS: ADC maps had higher visualization scores than b = 0 and b = 800 images (2.7 ± 0.5, 2.5 ± 0.6, and 2.4 ± 0.6 respectively, P<0.05). The mean ADC was higher in acute DVT than non-acute DVT (0.56 ± 0.17 × 10- 3 vs. 0.22 ± 0.12 × 10- 3 mm2/s, P<0.001). Using 0.32 × 10- 3 mm2/s as the cutoff, sensitivity and specificity for ADC to discriminate acute from non-acute DVT were 93 and 90% respectively. Sensitivity and specificity were 73 and 60% for rSI on b = 0, and 75 and 63% for rSI on b = 800. CONCLUSIONS: Readout segmented diffusion-weighted CMR derived ADC distinguishes acute from non-acute DVT. TRIAL REGISTRATION: This study is retrospectively registered. TRIAL REGISTRATION NUMBER: HUST-TJH-2015-146 .

Intravoxel incoherent motion diffusion MR and diffusion kurtosis imaging for discriminating atypical bone metastasis from benign bone lesion.

OBJECTIVES: To investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion MR and diffusion kurtosis imaging (DKI) in discriminating atypical bone metastasis from benign bone lesion in patients with tumors. METHODS: Patients with bone lesions in lower extremity suspected of metastases were enrolled in this prospective study. IVIM diffusion MR and DKI were performed before biopsy. Apparent diffusion coefficient (ADC), true diffusion (D), perfusion fraction (f) and perfusion-related pseudodiffusion (D*) were generated with IVIM, while mean kurtosis (MK) and mean diffusion (MD) generated with DKI. Two radiologists blinded to pathology results separately measured these parameters for each lesion through drawing region of interest. Intraclass correlation coefficient was used to determine the inter-reader viability in measurement. The patients with pathology-confirmed metastasis or benign lesion were analyzed. The Mann-Whitney test was used to compare IVIM and DKI parameters between metastasis group and benign lesion group. Receiver operating characteristic curves were constructed to evaluate the ability of discrimination. RESULTS: Bone lesions from 28 patients (metastasis, n = 15; benign lesion, n = 13; mean age = 55 years; age range, 34~77) were analyzed with IVIM and DKI. Intraclass correlation coefficient was greater than 0.8 for all parameters. ADC, D and MD were significantly lower in metastases versus benign lesions (p <0.05). MK and f value were significantly higher in metastases versus benign lesions (p<0.05). D* was not significantly different between the two groups (p>0.05). Areas under curve for ADC, D, f, MK and MD were 0.935, 0.939, 0.891, 0.840 and 0.844 respectively. CONCLUSIONS: IVIM and DKI derived parameters distinguish between atypical bone metastasis and benign bone lesion in selected patients with tumors. ADVANCES IN KNOWLEDGE: Bone metastasis and benign bone lesion differ in water molecular diffusion. Intravoxel incoherent motion derived true diffusion distinguishes between atypical bone metastasis and benign lesion.

Protective effect of troxerutin and cerebroprotein hydrolysate injection on cerebral ischemia through inhibition of oxidative stress and promotion of angiogenesis in rats.

Brain ischemia, including cerebral ischemia and cerebrovascular ischemia, leads to poor oxygen supply or cerebral hypoxia, and causes brain tissue death or cerebral infarction/ischemic stroke. The troxerutin and cerebroprotein hydrolysate injection (TCHI), is widely applied in China to improve blood supply in ischemic brain tissues and to enhance neuroprotective effects in clinical practice. However, the benefits and detailed underlying mechanism elaborating the effectiveness of TCHI in cerebrovascular diseases require further investigation. Therefore, in the present study, experimental in vivo and in vitro models were employed to investigate the potential mechanisms of TCHI on cerebral ischemic injury. The results demonstrated that TCHI increased the lactate dehydrogenase levels in the brain homogenate and conversely decreased lactic acid levels. TCHI was further observed to significantly increase superoxide dismutase activity and decrease malondialdehyde levels in ischemic brain tissues. In addition, TCHI significantly induced vascular maturation processes, including proliferation, adhesion, migration and tube formation in cultured human umbilical vein endothelial cells. Additionally, TCHI significantly stimulated microvessel formation in the rat aortic ring and chick chorioallantoic membrane assays. Taken together, these results provided strong evidence that TCHI stimulated angiogenesis at multiple steps, and indicated that TCHI attenuated cerebral ischemic damage through the amelioration of oxidative stress and promotion of angiogenesis.

Intravoxel incoherent motion and diffusion kurtosis imaging for discriminating soft tissue sarcoma from vascular anomalies.

To investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) in discriminating soft tissue sarcoma from vascular anomalies.Twenty-two patients with lower extremity soft tissue sarcoma and 15 patients with lower extremity vascular anomalies underwent IVIM-DWI and DKI. IVIM model generated true diffusion (D), perfusion fraction (f), and pseudo-diffusion coefficient (D). DKI model generated mean kurtosis (MK) and mean diffusion (MD). These parameters were measured by 2 radiologists separately through drawing region of interest. Intraclass correlation coefficient (ICC) was calculated to evaluate the inter-reader viability in measurement. The Mann-Whitney test was used to compare the parameters between vascular anomalies and soft tissue sarcoma. Receiver operating characteristic curves were constructed for assessing diagnostic accuracies.ICC was more than 0.8 for apparent diffusion coefficient (ADC), D, D, f, MK, and MD. Mean ADC, D, and MD were significantly lower in soft tissue sarcoma versus vascular anomalies (P < .05). Mean D and f were not significantly different (P > .05). Soft tissue sarcoma had significantly higher MK than vascular anomalies (P < .05). Areas under curve for ADC, D, MK, and MD were 0.876, 0.885, 0.894, and 0.812, respectively.IVIM and DKI are feasible in discriminating soft tissue sarcoma from vascular anomalies.

Estrogen enhances tumor growth and angiogenesis indirectly via mediation of bone marrow­derived cells as well as directly through stimulation of tumor and endothelial cells.

Estradiol (E2) is a prime culprit for enhancing the progression of female hormone­related cancers. Bone marrow­derived cells (BMDCs) have been found to play a pivotal role in tumor growth. Estrogen receptors (ERs) are also found on certain subtypes of BMDCs, in addition to endothelial cells (ECs) and certain tumor cells. However, the role of BMDCs in E2­induced tumor biology is still unclear. Thus, the effects of E2 on ER­negative 4T1 breast cancer growth, the mobilization and recruitment of BMDCs, and interactions among BMDCs, ECs, and 4T1 cells were investigated. The results showed that E2 potentiated 4T1 tumor growth and angiogenesis in mice subjected to sham operation, ovariectomy (OVX), or OVX and E2 replacement treatment. E2 supplementation in mice with OVX upregulated the transcription of stromal cell­derived factor­1 (SDF­1) mRNA in tumor tissues and enhanced the recruitment of BMDCs into tumor tissues in vivo. E2 deficiency significantly decreased proangiogenic CXCR4+, ß3+, Sca­1+ and CXCR4+ß3+ BMDCs circulating in the peripheral blood. Cell­based system analyses showed that E2 augmented the transcription of ß3 mRNA in ECs, increased the adhesion of BMDCs to ECs. In addition, E2 enhanced the BMDC­induced EC proliferation and migration, the BMDC­induced 4T1 proliferation and the 4T1­stimulated EC proliferation in addition to enhancing the proliferation of tumor cells and the migration of ECs in vitro. Therefore, E2 enhanced the growth of breast tumors by stimulating tumor cells and ECs directly, as well as by increasing proangiogenic BMDC mobilization and recruitment leading to augmentation of the tumor and EC functions indirectly by cell proliferation assay. These findings reveal a separate mechanism via which E2 promotes the growth of female hormone­dependent tumors, which may be useful in explorations of new therapies for related cancers.

Role for imaging in spondyloarthritis.

INTRODUCTION: Despite major progress in the imaging diagnosis of spondyloarthritis (SpA), the relative advantages of various available imaging techniques remain unclear. The aim of this study is to assess the current use of imaging in the diagnosis of SpA and to provide suitable recommendations for the use of imaging as an outcome measure as defined in the Assessment in SpondyloArthritis international Society (ASAS) criteria. EVIDENCE ACQUISITION: A systematic literature search regarding imaging in SpA was performed. Articles were assessed by two reviewers to identify and summarized key information pertaining to imaging in SpA. EVIDENCE SYNTHESIS: The search identified 180 relevant articles. Conventional radiography (CR) (17 articles), ultrasound (US) (26 articles), conventional computed tomography (CT) (13 articles), spectral computed tomography (spectral CT) (2 articles), bone scintigraphy (24 articles), and magnetic resonance imaging (MRI) were assessed (98 articles). Sacroiliitis and enthesitis were the major imaging findings in SpA. Multiple studies assessed the feasibility, validity, or differences among imaging modalities for the diagnosis of SpA; however, comprehensive assessments were not available due to a paucity of prospective imaging studies. CR is a widely available, inexpensive initial approach to evaluate patients with suspected SpA. CT enables assessment of structural changes from chronic sacroiliitis including bony erosions, subchondral sclerosis, joint space narrowing, and ankyloses; however, both CR and CT modalities are insensitive for demonstrating early enthesitis and sacroiliitis in SpA. US mainly identifies appendicular enthesitis but is more limited with respect to the sacroiliac joints. Bone scintigraphy can identify sacroiliac joint lesions and semi-quantitatively assess active sacroiliitis. MRI optimally evaluates not only early enthesitis and sacroiliitis of SpA but also chronic structural changes to the sacroiliac joints. CONCLUSIONS: More than one modality may be required for diagnostic and assessment of SpA depending upon disease characteristics and evolution. CR is a suitable initial examination while MRI is able to detect both early and late changes of SpA. A combination of CR and MRI is recommended for the diagnosis and assessment of SpA.

Granulocyte-macrophage colony-stimulating factor increases tumor growth and angiogenesis directly by promoting endothelial cell function and indirectly by enhancing the mobilization and recruitment of proangiogenic granulocytes.

Granulocyte-macrophage colony-stimulating factor has been widely used as an adjuvant therapy for cancer patients exhibiting myelosuppression induced by chemotherapy or radiotherapy. However, the effects of granulocyte-macrophage colony-stimulating factor on tumor growth, as well as its precise mechanism, are still controversial due to inconsistent evidence. This study investigated the effect of exogenous granulocyte-macrophage colony-stimulating factor on the growth of B16 melanoma, S180 sarcoma, and U14 cervical carcinoma in mice. The angiogenesis and recruitment of bone-marrow-derived cells were analyzed in tumor tissues. Interactions among granulocyte-macrophage colony-stimulating factor, bone-marrow-derived cells, and B16 tumor cells were investigated in vitro. Proangiogenic types of bone-marrow-derived cells in blood were assessed both in vivo and in vitro. The results showed that granulocyte-macrophage colony-stimulating factor markedly facilitated the growth of B16 and S180 tumors, but not U14 tumors. Granulocyte-macrophage colony-stimulating factor increased the densities of blood vessels and the number of bone-marrow-derived cells in B16 tumor tissues. The granulocyte-macrophage colony-stimulating factor-induced enhancement of tumor cell proliferation was mediated by bone-marrow-derived cells in vitro. Meanwhile, a distinct synergistic effect on endothelial cell function between granulocyte-macrophage colony-stimulating factor and bone-marrow-derived cells was observed. After separating two types of bone-marrow-derived cells, granulocyte-macrophage colony-stimulating factor-induced enhancement of tumor growth and angiogenesis in vivo was mediated by proangiogenic cells in granulocytes, but not monocytes, with CD11b+, vascular endothelial growth factor receptor 2, and C-X-C chemokine receptor 4 granulocytes possibly involved. These data suggest that granulocyte-macrophage colony-stimulating factor contributes to the growth and angiogenesis of certain types of tumor, and these mechanisms are probably mediated by proangiogenic cells in granulocytes. Applying granulocyte-macrophage colony-stimulating factor may attenuate the antitumor effects of chemotherapy and radiotherapy in certain types of tumor.