scholarly journals Remodeling tumor microenvironment by liposomal co-delivery of DMXAA and simvastatin inhibits malignant melanoma progression

2021 ◽  
Author(s):  
Valentin Florian Rauca ◽  
Laura Patras ◽  
Lavinia Luput ◽  
Emilia Licarete ◽  
Vlad Alexandru Toma ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Novel Therapy ◽  
Drug Induced ◽  
Angiogenic Therapy ◽  
Melanoma Model ◽  
M1 Phenotype

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy inhibited almost totally the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and induction of a pro-apoptotic state in the tumor microenvironment (TME). These effects were favoured by the partial re-education of TAMs towards a M1 phenotype and maintained via suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the tumor microenvironment, by suppressing its most important malignant biological capabilities.

scholarly journals Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Valentin-Florian Rauca ◽  
Laura Patras ◽  
Lavinia Luput ◽  
Emilia Licarete ◽  
Vlad-Alexandru Toma ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Combined Therapy ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Novel Therapy ◽  
Drug Induced ◽  
Angiogenic Therapy ◽  
Melanoma Model

AbstractAnti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.

Tumor DDR1 deficiency reduces liver metastasis by colon carcinoma and impairs stromal reaction

2021 ◽  
Author(s):  
Irene Romayor ◽  
Joana Márquez ◽  
Aitor Benedicto ◽  
Alba Herrero ◽  
Beatriz Arteta ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Tumor Microenvironment ◽  
Tumor Development ◽  
Immunohistochemical Analysis ◽  
Tyrosine Kinase Receptor ◽  
Ecm Remodeling ◽  
Cell Functions ◽  
Tumor Tissues

Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the result of complex interaction between the tumor cell, the collagenous extracellular matrix (ECM) and the hepatic sinusoidal cells (SCs). Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by collagen and a bad prognosis factor in cancer. DDR1 signaling regulates key cell functions for tumor development, such as proliferation, migration, invasion and metalloproteinases (MMPs) secretion. However, the mechanisms underlying the implication of DDR1 in the conformation of the metastatic niche in the liver remain poorly known. In this study, we used an experimental model of liver metastasis from CRC to investigate the role of DDR1 in the context of the pro-metastatic crosstalk between tumor cells and the hepatic stroma. Bioinformatics and immunohistochemical analysis revealed that DDR1 was highly expressed in tumor tissues from patients with primary CRC and hepatic CRC metastasis. Besides, DDR1 overexpression was associated with poor outcome. In vitro, SCs-derived soluble factors promoted DDR1 phosphorylation and MMP2 production by CRC cells. In vivo, tumor DDR1 participated in hepatic ECM remodeling by modulating the expression of collagen and MMP2, and stimulated the recruitment of stromal cells into the tumor microenvironment. In addition, tumor DDR1 favored SCs ability to modify the ECM organization by controlling the expression of collagen and MMPs. Altogether, our results show that tumor DDR1 plays an important role in the desmoplastic response of hepatic tumor microenvironment during CRC invasion and growth.

scholarly journals Immunological response in the mouse melanoma model after local hyperthermia

2008 ◽  
pp. 459-465
Author(s):  
J Kubeš ◽  
J Svoboda ◽  
J Rosina ◽  
M Starec ◽  
A Fišerová
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cell ◽  
Immunological Response ◽  
B16f10 Melanoma ◽  
Mouse Melanoma Model ◽  
Melanoma Model ◽  
Release Assay ◽  
Activated Monocytes

Our study was aimed to characterize the phenotype and functional endpoints of local microwave hyperthermia (LHT, 42 °C) on tumor infiltrating and spleen leukocytes. The effectiveness of LHT applied into the tumor of B16F10 melanoma-bearing C57/BL6 mice was compared with anesthetized and non-treated animals. Subpopulations of leukocytes were analyzed using the flow cytometry, and the cytotoxic activity of splenocytes against syngeneic B16F10 melanoma and NK-sensitive YAC-1 tumor cell lines was evaluated in 51Cr-release assay. Similarly, the in vitro modification of the heat treatment was performed using healthy and melanomabearing splenocytes. We found a 40 % increase of activated monocytes (CD11b+CD69+) infiltration into the tumor microenvironment. In the spleen of experimental animals, the numbers of cytotoxic T lymphocytes (CTLs-CD3+CD8+) and NK cell (CD49b+NK1.1+) raised by 22 % and 14 %, respectively, while the NK1.1+ monocytes decreases by 37 %. This was accompanied by an enhancement of cytotoxic effector function against B16F10 and YAC-1 targets in both in vivo and in vitro conditions. These results demonstrate that LHT induces better killing of syngeneic melanoma targets. Furthermore, LHT evokes the homing of activated monocytes into the tumor microenvironment and increases the counts of NK cells and CTL in the spleen.

H3K9me3-Governed Senescence In Tumor Development and Lymphoma Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 345-345 ◽  
Author(s):  
Julia Kase ◽  
Jan Dörr ◽  
Yong Yu ◽  
Maja Milanovic ◽  
Sujuan Ji ◽  
...  
Keyword(s):  
Overall Survival ◽  
Conflicts Of Interest ◽  
Tumor Development ◽  
B Cell Lymphoma ◽  
S Phase ◽  
Brdu Incorporation ◽  
Drug Induced ◽  
Human Diploid Fibroblasts

Abstract Introduction Premature senescence, a terminal cell-cycle arrest condition of viable cells in response to acute cellular stresses such as oncogenic activation or DNA-damaging anticancer therapy, is characterized by S-phase entry-controlling histone H3 lysine 9 trimethylation (H3K9me3). Previously, we reported an essential, tumor-suppressive role for the H3K9 histone methyltransferase Suv39h1 in oncogene-induced senescence (OIS) as a barrier to lymphoma development in vivo (Braig-M et al., Nature, 2005). In the current study, we focused, in addition to Suv39h1, on the H3K9-active demethylases LSD1 and JMJD2C in both OIS and therapy-induced senescence (TIS). Methods Human diploid fibroblasts (HDFs) and mouse embryo fibroblasts (MEFs) were stably transfected with H-RasG12V to induce OIS. S-phase-promoting E2F target gene control by H3K9me3 was analyzed by chromatin immunoprecipitation. Transformation was assessed by anchorage-independent colony formation in vitro and tumor development in nude mice. To establish TIS, primary Eµ-myc transgenic mouse lymphoma cells, retrovirally transduced with bcl2 to block apoptosis, were exposed to adriamycin in vitro or cyclophosphamide in vivo. Senescence was analyzed by staining for senescence-associated b-galactosidase activity (SA-b-gal), Ki67 and BrdU incorporation. Lymphoma formation and treatment in vivo were monitored by luciferase and GFP imaging, SA-b-gal/Ki67 staining in situ, and overall survival was assessed by Kaplan Meier analysis. Results H3K9-active demethylases – like overexpression of a dysfunctional H3R9 mutant – blocked cellular senescence, and permitted direct transformation under oncogenic Ras. In Myc-driven lymphomas, either loss of Suv39h1 or overexpression of LSD1 or JMJD2C cancelled TIS in vitro and in vivo. Notably, H3K9me3-impaired lymphomas resembled control lymphomas in their proliferation rate and sensitivity to drug-induced apoptosis, but displayed significantly shorter progression-free and overall survival after chemotherapy. Extended data sets on LSD1 and JMJD2C expression in human diffuse large B-cell lymphoma samples and their correlation to treatment outcome will be presented at the meeting. Conclusion The data underscore the essential albeit dynamic role of the H3K9me3 mark in OIS and TIS, and unveil the oncogenic potential of H3K9 demethylases, thereby providing a mechanistic basis for JMJD2C- or LSD1-targeting strategies in lymphoma therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hypoxic stress suppresses lung tumor-secreted exosomal miR101 to activate macrophages and induce inflammation

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Jie Li ◽  
Peng Xu ◽  
Di Wu ◽  
Minjie Guan ◽  
Xuanwen Weng ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Lung Tumor ◽  
Hypoxia Inducible Factor ◽  
Lung Squamous Cell Carcinoma ◽  
In Vitro Study ◽  
The Cancer Genome Atlas ◽  
Hypoxic Stress

AbstractHypoxia promotes inflammation in the tumor microenvironment. Although hypoxia-inducible factor 1α (HIF1α) is a master modulator of the response to hypoxia, the exact mechanisms through which HIF1α regulates the induction of inflammation remain largely unclear. Using The Cancer Genome Atlas Lung Squamous Cell Carcinoma (TCGA-LUSC) database, we divided patients with LUSC into two groups based on low or high HIF1α expression. After analyzing the differentially expressed genes in these two groups, we found that HIF1α was positively correlated with interleukin 1A (IL1A) and IL6 expression. Our in vitro study showed that hypoxic stress did not induce IL1A or IL6 expression in tumor cells or macrophages but dramatically enhanced their expression when co-cultured with tumor cells. We then investigated the effect of tumor-derived exosomes on macrophages. Our data suggested that the changes in miR101 in the tumor-derived exosomes played an important role in IL1A and IL6 expression in macrophages, although the hypoxic stress did not change the total amount of exosome secretion. The expression of miR101 in exosomes was suppressed by hypoxic stress, since depletion of HIF1α in tumor cells recovered the miR101 expression in both tumor cells and exosomes. In vitro, miRNA101 overexpression or uptake enriched exosomes by macrophages suppressed their reprogramming into a pro-inflammatory state by targeting CDK8. Injection of miR101 into xenografted tumors resulted in the suppression of tumor growth and macrophage tumor infiltration in vivo. Collectively, this study suggests that the HIF1α-dependent suppression of exosome miR101 from hypoxic tumor cells activates macrophages to induce inflammation in the tumor microenvironment.

Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

2018 ◽  
pp. 41-46
Author(s):  
А.А. Раецкая ◽  
С.В. Калиш ◽  
С.В. Лямина ◽  
Е.В. Малышева ◽  
О.П. Буданова ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Development ◽  
Significant Inhibition ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Solid Carcinoma ◽  
Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

scholarly journals Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

2013 ◽  
Vol 28 (5) ◽  
pp. 1101-1116 ◽  
Author(s):  
Zhican Wang ◽  
Yvonne S Lin ◽  
Leslie J Dickmann ◽  
Emma-Jane Poulton ◽  
David L Eaton ◽  
...  
Keyword(s):  
Drug Induced ◽  
Cyp3a4 Induction

scholarly journals TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Qingxia Wei ◽  
Olivia Singh ◽  
Can Ekinci ◽  
Jaspreet Gill ◽  
Mira Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Gene Expression Signature ◽  
Endothelial Activation ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Mouse Glioma ◽  
Novel Therapeutic ◽  
Tumor Area

AbstractOne of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

scholarly journals C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Kosuke Sasaki ◽  
Shigetsugu Takano ◽  
Satoshi Tomizawa ◽  
Yoji Miyahara ◽  
Katsunori Furukawa ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Binding Protein ◽  
Combined Treatment ◽  
Tumor Infiltrating Lymphocytes ◽  
Pdac Cell ◽  
Α Chain ◽  
Infiltrating Lymphocytes

Abstract Background Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. Methods We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. Results Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. Conclusions These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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